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WORKS  OF  ALFRED  I.  COHN 

PUBLISHED   BY 

JOHN   WILEY  &  SONS. 


Indicators  and  Test-papers. 

Their  Source,  Preparation,  Application,  and  Tests 
for  Sensitiveness.  With  Tabular  Summary  of  the  Ap- 
plication of  Indicators.  Second  Edition,  Revised  and 
Enlarged.     i2mo,  ix  +  267  pages.     Cloth,  $2.00. 

Tests  and  Reagents. 

Chemical  and  Microscopical,  known  by  their 
Authors'  Names;  together  with  an  Index  of  Subjects. 
8vo,  iii  +  383  pages.     Cloth,  $3.00. 

TRANSLA  TIONS. 

Fresenius's  Quantitative  Chemical  Analysis. 

New  Authorized  Translation  of  the  latest  German 
Edition.  In  two  volumes.  By  Alfred  I.  Cohn, 
Phar.D.  Recalculated  on  the  basis  of  the  latest  atomic 
weights,  and  also  greatly  amplified  by  the  translator. 
8vo,  2  vols.,  upwards  of  2000  pages,  280  figures.  Cloth, 
$12.50. 

Techno=ChemicaI  Analysis. 

By  Dr.  G.  Lunge,  Professor  at  the  Eidgenossische 
Polytechnische  Schule,  Zurich.  Authorized  Transla- 
tion by  Alfred  I.  Cohn,  Phar.D.  i2mo,  vii  +  136  pages, 
16  figures.     Cloth,  $1.00. 

Toxins  and  Venoms  and  Their  Antibodies. 

By  Em.  Pozzi-Eso.t.  Authorized  Translation  by 
Alfred  I.  Cohn,  Phar.D.  nmo,  vii+  101  pages.  Cloth, 
$1.00,  net. 


THE 

TOXINS  AND  VENOMS 

AND   THEIR   ANTIBODIES 


BY 

EM.    POZZI-ESCOT 

AUTHORIZED     TRANSLATION 

BY 

ALFRED   I.    COHN,   Phar.  D. 


FIRST    EDITION 
FIRST    THOUSAND 


NEW  YORK 

JOHN   WILEY    &    SONS 

London  :    CHAPMAN    &    HALL,    Limited 

1906 


2-2--   3   0  o  o  5~ 


Copyright,  1906 

BY 

ALFRED  I.   COHN 


ROBERT    DRUMMOND.    PRINTER,    NEW   YORK 


INTRODUCTION. 


Our  knowledge  of  the  toxins  is  of  quite  recent 
date.  It  is  hardly  twenty  years  since  we  began  to 
acquire  a  knowledge  of  the  facts  that  are  detailed 
in  this  volume,  and  to  which  modern  medicine  owes 
its  most  recent  and  marvelous  progress,  particularly 
in  serotherapy. 

In  this  volume  we  have  studied,  besides  the  true 
toxins — substances  of  cellular  origin  and  of  albu- 
minoid nature  and  unknown  composition — other 
toxic  substances,  the  nitrogenized  alkaloidal  bases 
introduced  into  science  through  the  researches  of 
Selmi,  Armand  Gautier,  and  von  Behring,  and 
which  are  highly  hydrogenized  nitrogenous  crys- 
tallizable  principles  of  definite  chemical  compo- 
sition— the  products  of  the  more  or  less  advanced 
breaking  down  of  albuminoids. 

Although  these  principles  differ  widely,  by  rea- 
son of  their  physiological  properties  as  a  whole, 
from  the  toxic  albuminoids,  or  true  toxins,  it 
appears  proper  to  consider  them  as  products  of 


m 


IV  INTRODUCTION. 

the  advanced  decomposition  of  these  toxins — and 
in  this  respect  their  study  becomes  imperative,  the 
more  so  as  they  are  very  frequently  encountered 
together  with  the  toxins,  particularly  in  serpent- 
venoms,  where  their  action  is  exerted  in  addition 
to  that  of  the  true  toxins. 

In  the  first  volume  of  this  collection  we  dwelt 
on  the  essentially  reducing  nature  of  the  cellular 
functionation.  To  this  functionation — rcausing  the 
splitting  up  or  decomposition  by  hydrolysis  of 
nitrogenized  albuminoid  foods — is  due  the  forma- 
tion of  these  toxic  basic  products  within  the  organ- 
ism, whether  normally,  or  because  of  certain  patho- 
logical conditions. 

This  alone  suffices  to  show  that,  during  physio- 
logical life,  oxygen  plays  an  essentia  ly  antitoxic 
role  within  the  organism. 

It  is  hoped  that  this  succinct  resum£,  which  it 
has  been  sought  to  make  as  clear  as  possible,  will 
be  of  service  to  those  who,  while  not  scientists 
actively  engaged  in  scientific  progress,  desire  to 
be  abreast  of  the  knowledge  of  modern  evolution, 
but  yet  are  not  in  a  position  to  consult  original 
papers  or  large  treatises. 


CONTENTS. 


PAGB 

Introduction iii 


PART    I. 

GENERALITIES   REGARDING   TOXINS    AND 
ANTITOXINS. 

CHAPTER   I. 

Alkaloidal  Toxins,  Ptomaines,  and  Leucomaines. 

Alkaloidal  products  of  cellular  life i 

Ptomaines 4 

Physiological  action 5 

Extraction 5 

Classification,  etc 7 

Leucomaines 10 

Xanthic  leucomaines 12 

Crcatinic  leucomaines 13 

Neurinic  leucomaines 13 

Indeterminate  leucomaines 14 

CHAPTER   II. 
Toxins  and  Antitoxins. 

Toxins k 

Action  of  pathogenic  bacteria j6 

Action  "I  toxins 17 

Nature  of  toxins ^ 

v 


VI  CONTENTS. 

PAGE 

Origin  of  toxins 20 

Autointoxications 21 

General  mode  of  action 23 

Constitution  of  toxins;    Ehrlich's  theory 24 

Means  of   defense  possessed  by  the  organism  against 

the  action  of  toxins 28 

Pasteur's  vaccination  method 30 

Virus  action 30 

Phagocytosis 32 

Antitoxins 33 

Mode  of  action 35 

Formation ;  Ehrlich's  theory 38 

Serotherapy,  ,  ,  , , , , .......♦,,....  41 

PART  II. 

THE  TOXINS  PROPER. 
CHAPTER  III. 

I.  Vegetable  and  Animal  Toxins 42 

Abrin 42 

Ricin 44 

Robin 45 

Toxicity  of  the  vegetable  diastases.. 45 

II.  Toxins  from  Mushrooms 46 

Phalline 48 

Symptomatology 49 

Antidiastases •  • 51 

III.  Animal  Toxins 53 

Peptotoxin 53 

Alime  tary  Intoxications 55 

Urinary  toxins 57 

Variation  of  urinary  toxicity 59 

Autointoxications  (animal) 60 

Glandular  secretions 62 

Suprarenal  capsules 63 


CONTENTS.  Vli 

CHAPTER    IV. 
The  Microbial  Toxins 

PAGE 

Pyogenic  and  pyretogenic  properties 66 

Anthrax  toxin 67 

Tubercular  toxin 69 

Diphtheria  toxin 71 

Tetanus  toxin 76 

Mallein 79 

Typhoid  toxin 80 

Cholera  toxin 82 

CHAPTER   V. 

The  Venoms. 

General  nature  of  venoms 85 

Venomous  serpents 87 

Nature  of  serpent-venoms.  .  , 88 

Natural  immunity  towards  serpent-venoms 90 

Artificial  immunity  towards  serpent  venoms 91 

Venoms  of  batrachims  and  saurians   92 

Fish-poisons 95 

Poisons  of  the  hymenoptera 96 

Poisons  of  scorpions 97 

Poisonous  blood  and  serums    98 

Poisonous  meats  . , 100 


TOXINS   AND   VENOMS. 


PART  I. 


GENERALITIES  REGARDING  TOXINS  AND 
ANTITOXINS. 


CHAPTER  I. 

ALKALOIDAL   TOXINS.    PTOMAINES   AND 
LEUCOMAINES. 

Alkaloidal  Products  of  Cellular  Life. 

Before  entering  upon  the  study  of  the  true 
toxins,  which  are  products  of  an  alkaloidal  nature 
and  of  unknown  composition,  it  is  necessary  to 
say  a  few  words  regarding  the  most  definite  of 
the  toxic  alkaloidal  principles  that  are  frequently 
encountered  under  various  conditions,  conjointly 
with  the  true  toxins,  particularly  in  venoms,  and 
which,  furthermore,  are  closely  allied  to  these  albu- 
minoid toxins. 


2  TOXINS  AND    ANTITOXINS. 

These  principles  are  formed  in  essentially  redu- 
cing media,  whether  it  be  within  the  body  of  the 
organism,  and  by  the  simple  exercise  of  its  nor- 
mal function,  in  which  case  the  principles  bear 
the  generic  name  leucomaines  * ;  or  whether  due  to 
the  action  of  anaerobic  microbes,  when  they  are 
designated  as  ptomaines,  f  These  basic  principles, 
which  are  essentially  the  products  of  cellular  secre- 
tion, are  usually  toxic,  and  sometimes  even  ex- 
tremely to. 

As  we  shall  presently  see,  ptomaines  are  essen- 
tially products  formed  during  putrefactive  fermen- 
tation. The  toxic  properties  of  extracts  from  the 
cadaveric  fluids  have  long  been  known.  Already 
in  1838  Panum  %  had  met  with  these  products 
in  snake  venoms.  Bergmann  and  Schmiedberg  §  in 
1868  isolated  from  septic  pus  a  toxic  substance 
which  they  named  sepsin;  and  almost  at  the  same 
time  Zuelzer  and  Sonnenschein  ||  reported  having 
isolated  from  anatomical  preparations  an  alkaloid 
possessing  mydriatic  properties.  It  is,  however, 
due   particularly   to    the    researches    of   Selmi  and 

*  Armand  Gautier:  Sur  les  leucomaines,  ncmveaux  alcaloides, 
derives  de  la  transformation  des  substances  proteiques  des  tissus 
vivants.     Bull.  Soc.  Chim.,  2e  serie,  xliii,  p.  158. 

f  Armand  Gautier:  '  'Communication  sur  les  bases  d'origine 
putrefactive."     Bull.  Soc.  Chim.  (2),  xxxvn,  p.  305. 

%  Virchow  Archiv.,  x,  p.  301. 

§  Medic.  Centralblatt,  1868,  p.  497. 

||  Berlin.  Klin.  Woch.,  1869,  No.  2, 


ALKALOIDAL  TOXINS.  3 

Armand  Gautier  that  we  arc  now  so  well  informed 
regarding  these  toxic  principles. 

The  labors  of  Armand  Gautier  were  first  pub- 
lished in  his  TraitS  de  Chimic  Appliquec  h  la  Phy- 
siologic; those  of  Selmi  in  the  Actes  de  V Academic 
de  Bologne. 

At  first  sight,  there  appears  to  be  a  great  difference 
between  these  alkaloidal  bases,  the  ptomaines  and 
leucomaines,  and  the  albuminoid  toxins  proper. 
The  toxic  bases  of  the  first  two  groups  are  quite 
definite  chemical  products  which  can  be  gener- 
ally obtained  quite  pure,  and  frequently  in  crys- 
talline form.  The  toxins  proper,  on  the  other 
hand,  are  highly  complex  albuminoid  substances 
which  greatly  resemble  the  true  diastases  in  all 
their  properties. 

Nevertheless,  between  the  toxic  alkaloids, 
ptomaines  and  leucomaines,  and  the  toxic  albu- 
minoids, or  more  properly  toxins,  there  exists  no 
absolutely  sharp  line  of  demarcation,  but  there  is 
a  gradual  passage  from  the  one  to  the  other  by 
every  intermediary  grade,  as  a  result  of  the  break- 
ing down  of  the  albuminoid  molecule. 

We  shall  see,  moreover,  as  we  proceed,  that 
these  substances  are  formed  under  coexistent  cir- 
cumstances, and  that  they  are,  hence,  found  to- 
gether, whether  it  be  in  virus  or  in  snake  venom. 

We  will  first  consider  the  ptomaines,  and  then 
the  leucomaines. 


TOXINS  AND  ANTITOXINS. 


Ptomaines. 


This  name  is  more  specially  reserved  to  desig- 
nate those  alkaloidal  substances,  generally  highly 
hydrogenized,  that  are  formed  outside  the  organism, 
from  the  fermentative  action  of  anaerobic  microbes 
on  albuminoid  substances. 

These  bases  are  generally  volatile,  with  an  intense 
and  tenacious  purulent  odor;  often,  however,  they 
possess  a  floral  odor  (aubepine,  syringa),  and  even 
like  that  of  musk.  They  combine  readily  with 
acids  and  with  the  chlorides  of  the  heavy  metals, 
yielding  crystallizable  salts. 

The  ptomaines  afford  no  specific  reaction  whereby 
they  may  be  readily  identified ;  and  their  identifica- 
tion is  effected  only  after  a  painstaking  analysis. 

We  must  here  call  attention,  however,  to  several 
of  their  more  common  properties,  beginning  with 
their  basic  character,  their  oxidizability  by  the  air 
and  consequently  their  well-defined  reducing  power 
— a  property  that  led  Selmi  to  propose  a  mixture 
of  ferric  chloride  and  potassium  ferricyanide  as  a 
reagent  for  their  detection.*  They  are  precipitated 
by  all  the  general  reagents  for  the  vegetable  alka- 
loids. Selmi  has  given  several  reactions,  such  as 
those  afforded  by  sulphuric,  hydrochloric,  and 
nitric  acids,  which  appear,  however,  to  apply  much 

*  Sulle  ptomaine  od  alcaloidi  cadaverici.     Bologne,  clxxxvii, 

p.  XX. 


ALKALOIDAL  TOXINS.  5 

more  to  the  impurities  present  than  to  the  bases 
themselves. 

The  physiologieal  action  of  these  bases  varies 
greatly;  in  some  the  action  is  an  extremely  t<»xie 
one,  as  in  the  case  of  neurine  and  muscarine, 
which  are  true  ptomaines;  there  are  others,  such 
as  cadaverine  and  putrescine,  which  are  quite 
innocuous.  The  physiological  action  of  these  bases, 
like  that  of  the  true  toxins,  is  studied  by  making 
hypodermic  injections  of  solutions  of  the  bases  in 
healthy  animals,  such  as  guinea-pigs,  rabbits,  and 
dogs. 

In  animals,  the  principal  phenomena  observed  by 
Selmi  to  follow  the  injection  of  the  substances  are 
the  following:  At  first  dilatation  of  the  pupil,  then 
constriction ;  tetanic  convulsions,  soon  followed  by 
muscular  relaxation,  and  retardation,  rarely  acceler- 
ation, of  heart-beat ;  absolute  loss  of  cutaneous  sen- 
sibility; loss  of  muscular  contractility;  paralysis  of 
the  vasomotors ;  greatly  retarded  respiration  ;  stupor, 
followed  by  death  with  the  heart  in  systole. 

It  must  be  observed  that  in  a  number  of  cases 
where  toxic  researches  had  been  made  in  the  past, 
these  bases  had  been  mistaken  for  poisons  which 
were  believed  to  have  been  introduced  into  the 
organism  with  criminal  intent.  No  one  will  ever 
know  how  many  have  fallen  victims  in  the  past  to 
ignorance  regarding  the  cellular  mechanism! 

The  extraction  of  these  bases  is  a  tedious  and 


6  toxins  and  Antitoxins. 

difficult  operation.  The  materials  must  first  be 
exhausted  with  water  slightly  acidulated;  then, 
after  precipitating  the  albuminoids  by  boiling  and 
defecating  by  adding  lead  acetate,  the  liquid  is  evap- 
orated to  one-half  its  volume  and  dialyzed  in  a 
vacuum.* 

Phosphomolybdate  is  then  added  to  the  dialyzed 
liquid,  and  the  precipitate  formed,  which  now  con- 
tains all  the  bases,  decomposed  by  boiling  with 
lead  acetate.  After  removing  the  excess  of  lead, 
there  is  thus  obtained  a  limpid  solution  of  all  the 
alkaloidal  bases  in  the  form  of  acetates.  These 
are  separated  by  alcohol  and  by  means  of  frac- 
tional precipitations  with  various  metallic  salts, 
depending  upon  the  known  properties  of  the  bases. 

In  order  to  facilitate  their  study,  the  ptomaines 
have  been  grouped  under  two  distinct  classes,  the 
one  embracing  the  cadaveric  or  putrefactive 
ptomaines,  of  undetermined  microbial  origin,  the 
other  containing  the  ptomaines  formed  by  microbes 
of  known  character.  Each  of  these  two  groups  is 
itself  divided  into  subgroups,  as  shown  in  the 
following  table: 

*  Armand  Gautier:  C.  rend,  de  I'Acade'mie  des  Sciences,  cxiv, 
p.  1256.     Ibid.,  xcvn,  p.  264,  and  xciv,  p.  1600. 


ALKALOIDAL   TOXINS. 


GROUP   I. 


CADAVERIC    PTOMAINES    OF   UNDETERMINED   MICROBLAL 
ORIGIN. 

a.  Amines. 

b.  Guanidines. 

c.  Oxamincs  (fatty  or  aromatic). 

d.  Amido  Acids. 

e.  Carbopyridic  Acids  and  analogues. 
/.  Undetermined  Ptomaines. 

GROUP   II. 

PTOMAINES   OF   KNOWN  MICROBIAL  ORIGIN. 

a.  Ptomaines  extracted  from  microbial  cells. 

b.  Ptomaines  from  pathological  urines. 

We  will  not  here  enter  upon  a  detailed  study  of 
the  bases  belonging  to  each  of  these  groups.  This 
subject  is  a  vast  one,  requiring  for  its  treatment 
a  volume  devoted  to  it  alone.  We  will  here  simply 
touch  upon  the  principal  properties  of  several  of 
the  bases  of  each  of  the  subgroups  named. 

Bases  of  Group  I. 

a.  Amines. — Among  these  we  find  nearly  all  the 
fatty  amines,  such  as  the  methylamines  and  the 
cyclic  alkaloids  such  as  pyridine.  They  are  formed 
particularly  by  the  putrefaction  of  fish. 

Certain  of  these  bases  are  very  toxic,   for  in- 


8  TOXINS   AND    ANTITOXINS. 

stance   trimethylene    diamine,    the   collidines,    and 
the  parvolines. 

b.  Guanidines. — Among  the  products  of  ordinary- 
putrefaction  there  has  been  found  so  far  only  methyl- 
guanidine,  C2H7N3.  This  is  a  highly  toxic  base 
of  which  0.2   Gm.  is  fatal  to  a  guinea-pig. 

c.  Oxamines. — Under  this  designation  the  fol- 
lowing bases  are  comprised:  i.  Neurine  bases; 
2.  oxygenized  aromatic  bases;  3.  bases  of  un- 
known constitution.  Amongst  them  we  find  neu- 
rine and  choline,  which  are  toxic,  and  betaine,  which 
is  innocuous.  They  are  found  particularly  in 
putrid  fish. 

d.  Amido  Acids. — These  ptomaines,  which  are 
usually  innocuous  in  small  quantities,  are  par- 
ticularly the  products  of  the  decomposition  of  albu- 
minoid substances.  Among  them  we  find  gly- 
cocoll,  leucine,  and  tyrosine,  as  members  of  this 
group. 

e.  Carbopyridic  and  Carboquinoleic  Acids. — So 
far  only  one  base  is  known  belonging  to  this 
group,  and  that  is  morrhuic  acid,  which  is  found 
in  the  decomposed  livers  of  codfish,  and  which 
is  a  powerful  appetizer  and  stimulant  in  disassimi- 
lation. 

/.  Undetermined  Ptomaines. — Under  this  head- 
ing are  classed  certain  undetermined  bases,  such  as 
those  found  in  normal  urines,  and  in  spoiled  meats 
and  bread. 


ALKALOIDAL   TOXINS.  9 

Bases  of  Group  II. 

a.  Ptomaines  Isolated  from  Cultures  of  Patho- 
genic Bacteria. — Bacterial  cultures  contain,  besides 
the  true  toxins,  a  certain  number  of  alkaloidal 
bases  which  sometimes  possess  considerable  toxicity. 

In  the  cultures  of  streptococcus  pyogenes  there 
are  found  trimethylamine  and  xanthic  bases;  in 
those  of  staphylococcus  pyogenes  aureus  are  found 
xanthic  bases  and  creatinine;  while  pyocyanine 
and  pyoxanthine  are  found  in  the  cultures  of 
bacillus  pyocyaneus,  etc. 

b.  Ptomaines  Isolated  from  Pathological  Urines. — 
Toxic  ptomaine  bases  have  been  found  in  the  urines 
of  a  large  number  of  diseases.*  It  is  quite  prob- 
able that  these  bases  are  the  results  of  a  general 
pathological  condition  due  to  some  bacterial  disease, 
the  toxic  products  of  which  are  eliminated  by  the 
kidneys. 

From  the  urines  of  epileptics  Griffiths  f  isolated 
a  colorless  base  crystallizing  in  prisms  having  the 
formula  C12H15N5O7,  and  which  was  found  to  be 
exceedingly  toxic;  the  same  investigator  isolated 
from  the  urines  of  eczematous  subjects  a  ptomaine 

*  Griffiths:  C.  rend.  de  V AcaJe'mie  des  Sciences,  cxv,  pp.  2S5 
and  667. 

t  E.  Pouchet:  Contribution  a  l'etude  des  maticrcs  ex- 
tractives de  l'urine,  These,  Paris,  1SS0;  Ibid.,  C.  rend,  de  1'Aca- 
de'nne desSc,  xcvn.p.  1560;  Bouchard:  Crend.buc.de Biolog., 
Aug.  12,  1S82. 


IO  TOXINS   AND   ANTITOXINS. 

which  he  named  eczemine*  and  which  is  also  highly 
toxic. 

In  certain  cases  of  cystinuria  there  are  found  in 
the  urine  sulphurized  ptomaines,  and  in  measles 
the  urine  contains  an  undetermined  ptomaine, 
rubedine,  which  is  very  poisonous.  Typhotoxine,  a 
very  toxic  ptomaine,  has  been  isolated  from  the 
urine  of  typhoid  patients ;  erysipeline,  a  hardly  less 
toxic  base,  exists  in  the  urine  of  erysipelatic  sub- 
jects; while  spasmotoxine,  tetanotoxine ,  and  teta- 
nine,  exceedingly  active  alkaloids,  are  found  in  the 
urines  of  tetanus  patients,  f 

As  a  general  rule,  all  abnormal  urines  contain 
toxic  bases;  the  kidneys  appear,  in  fact,  to  serve 
as  a  means  of  eliminating  the  toxic  products  that 
form  in  large  quantity  whenever,  and  for  whatever 
cause,  the  organism  ceases  to  functionate  nor- 
mally, whether  it  be  as  a  whole,  or  in'  any  one  of 
its  parts.  % 

Leucomaines.§ 

The  leucomaines  are  basic  substances,  nearly 
allied  to  the  ptomaines,  but  still  more  closely  re- 
lated  to  the  ureides.      They  are  formed   directly 

*  Griffiths:  C.  rend,  de  V Academic  des Sciences,  cxvi,  p.  1206. 

|  Brieger:  Untersuchungen  uber  die  Ptomaine,  dritten  Teil, 
p.  93;  Berichte  d.  D.  Chem.  Gesellschajt,  1886,  p.  3159;  1887, 
p.  69. 

X  Charrin:    Les  poisons  de  I 'urine:    Encyclopedie  Leaute\ 

§  Armand  Gautier:   Bull.  Acad,  de  Medecin  (2),  xv,  p.  115. 


ALKALOIDAL  TOXINS.  u 

or  indirectly  by  the  breaking  down  of  protoplasmal 

albuminoids.  The  agents  that  effect  the  break- 
ing down  are  the  hydrolyzing  ferments  of  the 
economy.  It  is  well  to  recall  here  that  these 
phenomena  of  hydrolyzation  occur  within  the  cell 
itself  and  in  a  practically  reducing  medium,  as  we 
have  already  stated.  The  inmost  mechanism  of 
these  phenomena  cannot  here  be  detailed;  it  will 
be  found  described  by  Armand  Gautier  in  the 
Chi m ic  Biologique,  and  in  his  work  Chimie  de  la 
Cellule  Vivante* 

The  extraction  of  these  bases  is  an  extremely  deli- 
cate operation.  It  is  necessary  to  operate  with  a 
large  quantity  of  substance,  say  50  kilos.  The  sub- 
stance is  finely  chopped,  then  exhausted  with  twice 
its  weight  of  water  acidulated  with  acetic  acid  (0.2 
Cc.  per  liter)  and  containing  a  trace  of  oil  of  mustard, 
which  is  intended  to  act  as  an  antiseptic.  The  albu- 
minoids are  precipitated  by  boiling,  the  solution  then 
filtered,  evaporated  in  a  vacuum  at  6o°  C,  and  the 
bases  extracted  with  95-per  cent,  alcohol. 

The  alkaloidal  bases  obtained  in  this  manner  are 
separated  by  crystallization  from  alcohol  or  by 
various  other  chemical  methods,  the  description  of 
which  we  will  not  enter  upon  here. 

In  order   to   facilitate  the    study  of   the   leuco- 

*  Armand  Gautii.r:  Lemons  de  chimie  biologique.  Published 
by  Masson;  Ibid.,  Chimie  de  la  cellule  vivante.  Also  published 
by  Masson. 


12  TOXINS   AND   ANTITOXINS. 

maines  they  are  classed  tinder  three  groups,  accord- 
ing to  their  chemical  affinities.  These  groups  are 
as  follows: 

i.  Xanthic  Leucomaines.  —  The  bases  of  this 
group  appear  to  have  a  composition  resembling 
that  of  uric  acid.  When  hydrolyzed,  they  yield 
urea  and  guanidine.  They  are  weak  bases,  and 
exhibit  both  basic  and  weakly  acid  properties. 
They  all  possess  the  common  characteristic  of  being 
precipitated  by  copper  acetate  in  acid  solution  with 
heat,  and  by  ammoniacal  silver  nitrate  in  the  cold. 

According  to  Kossel,  these  bases  are  derived 
from  the  nucleo-albumins  which  are  found  in 
the  cell  nuclei,  and  which  are,  as  we  know,  sub- 
stances rich  in  nitrogen  and  phosphorus. 

Among  the  bases  of  this  group  may  be  men- 
tioned adenine,  C5H5N5,  which  is  obtained  from 
infusions  of  tea.*  This  base  is  non-toxic;  it  was 
discovered  by  Kossel,  f  and  it  crystallizes  easily. 

Some  others  of  this  group  are: 

Guanine,  C5H5N5O,  non-toxic,  discovered  by 
Unger;  pseudo-xanthine,  obtained  from  muscular 
tissues;  sarcine,  C5H4N4O,  also  but  slightly  toxic, 
discovered  by  Scherer;  xanthine,  C5H4N4O2, 
which  is  found  in  many  urines,  and  which  acts  as  a 
stimulant   on   the   cardiac  muscles;    paraxanthine, 

*  Kruger:  Bull.  Soc.  Chim.  (3),  vin,  p.  687. 
t  Kossel:   Zeitschrift   fur  physiol.    Chim.,    x,    p.    248;    and 
Bull.  Soc,  Chim.  (3),  in,  p.  239. 


AI.KAI  <  »IDAL    TOXINS.  13 

C7II8N4O2,    a    toxic    base    found    in    certain    patho- 
logical   urines;    caffeine   and   theobromine,  powerful 

diuretic  bases;  and  carnine,  C7\\s\ .,<  ):;,  from  meat, 
a  muscular  stimulant  like  caffeine. 

2.  Creatinic  Leucomaines.  These  have  for  their 
type  guanidine;  they  differ  from  the  xanthic  bases 
in  that  they  are  not  precipitated  by  copper  acetate, 
but  frequently  are  by  ammoniacal  silver  nitrate. 
They  yield  double  salts  with  the  chlorides  of  zinc 
and  cadmium.  To  this  group  belong  glycocyaniuc, 
C3H7N302,  and  glycocyanidinc,  C3H7N3O,  both  very 
toxic;  creatine,  C4H9N3O2,  only  slightly  toxic; 
creatinine,  C4H7N3O;  lysatinc,  which  very  easily 
decomposes  to  form  urea;  lysatinine,  xanthocredtine; 
arginine,  a  vegetable  base,  etc. 

3.  Neurinic  Leucomaines. — These  have  none  of 
the  characteristics  of  the  preceding  bases;  their 
type  is  neurine,  a  highly  toxic  base  found  in  the 
brain,  nerves,  and  certain  fish  ova.  These  bases 
are  sometimes  normally  produced  by  the  animal 
economy,  and  are  also  frequently  the  result  of 
microbic  action.  They  are  the  result  of  the  simple 
phenomena  of  fermentative  hydrolyzation  of  pro- 
tagons  and  lecithins.  Among  these  bases  are 
choline,  a  weak  alkaloid,  and  bctainc,  which  appears 
to  be  non-toxic. 

The  former  has  the  formula  C5H15N02;  it  was 
discovered  by  Stocker.  Wurtz  synthesized  it  by 
combining   trimcthylaminc    and    glycol-monochlor- 


14  TOXINS  AND   ANTITOXINS. 

hydrine,  and  treating  the  resulting  hydrochloride 
with  silver  oxide.  Betaine,  C5HiiN02,  is  found  in 
beets;  it  was  discovered  by  Scheibler.  Neurine  is, 
chemically,  trimethylvinylammonium  hydrate. 

4.  Undetermined  Leucomaines.  —  Among  these 
bases  several  are  important  in  more  than  one 
respect.  For  instance  spermine,  which  is  found  in 
the  sperm,  is  a  strong  base  possessing  a  powerfully 
dynamic  and  tonic  action  on  the  nerves.  It  acts 
as  an  oxidizer.  Spermine  was  first  obtained  by 
Schreiner  *  from  the  sperm  of  mammifers  in  which 
it  occurs  as  a  phosphate.  It  has  the  formula 
C5Hi4N2.  It  was  physiologically  studied  by  Poehl, 
Tarchanoff,  Weljaminoff,  and  Joffroy.f  Plasmaine, 
a  toxic  base  found  in  the  blood  and  discovered 
by  R.  Wurtz,J  has  the  formula  C5Hi5N5;  prota- 
mine, from  fish  milt,  was  discovered  by  Micocher.§ 


*  Liebig's  Ann.  der  Chemie,  cxciv,  p.  68. 
f  Journ.  Soc.  Phys.  Chim.  Russe,  1893,  No.  2;    and  Bull.  Soc. 
Chim.  (3),  xii,  p.  243. 

%  Leucomaines  du  Sang  Normal,  These,  Paris,  1889. 

§  Jolt  reab.  de  Thierchen,  1874,  p.  341 ;   Picard,  Ibid.,  p.  355. 


CHAPTER   TT. 

TOXINS  AXI)   ANTITOXINS. 

We  have  already  seen,  in  the  preceding  chapter, 
that  the  microbes  and  the  cells  of  various  organisms 
arc  capable  of  secreting  definite  products  of  a 
toxic  nature  to  which  the  names  "ptomaines  "  and 
"  leucomaines  "  have  been  given.  Researches, 
which  were  begun  scarcely  twenty  years  ago, 
have  shown  that,  besides  these  crystallizable 
and  definite  products,  we  meet  with  basic  non- 
crystallizable  substances  of  unknown  composition, 
possessing  special  toxic  properties,  sometimes  even 
of  extreme  violence.  These  substances  have  been 
named  "toxins." 

At  first  this  generic  name  was  extended  toward 
indefinite  basic  organic  products  that  could  be 
isolated  from  tissues  and  tumors  both  normal  and 
abnormal;  later  on,  however,  the  name  was  ap- 
plied to  toxic  substances,  equally  indefinite,  isolated 
from  the  culture  media  of  microbes  and  the  active 
constituent  of  various  venoms. 

It  is  only  since  1885,  when  Charrin  called  at- 
tention  to  them,  that   investigations  began  to  be 

15 


1 6  TOXINS   AND  ANTITOXINS. 

made  regarding  them.  In  1888  Roux  and  Yersin,* 
in  their  beautiful  researches  on  diphtheria,  pointed 
out  the  diastatic  nature  of  the  properties  of  the 
active  albuminoid  matter  existing  in  the  cul- 
tures of  the  specific  bacilli  of  this  disease.  From 
that  period,  these  products  began  to  take  a  more 
and  more  prominent  place,  from  year  to  year,  in 
the  study  of  pathological  affections,  and,  by  develop- 
ing the  knowledge  of  immunity,  they  have  opened 
a  new  path  to  the  investigations  of  therapeutic 
technic. 

It  is  due  to  the  knowledge  of  these  principles  that 
we  have  learned  that  the  infectious  microbes,  far 
from  acting  as  they  were  believed  to  do  only  a  few 
years  ago,  and  which  Pasteur  strongly  maintained 
to  be  by  vital  parasitism — such  as  would  be  the 
case  with  the  carbonizing  bacteria  which,  according 
to  Pasteur,  act  by  diverting  the  oxygen,  or  causing 
capillary  embolisms — owe  their  pathogenic  action 
to  the  toxic  substances  which  are  the  products 
of  their  secretion,  and  which  spread  throughout 
the  organism,  even  though  the  microbe  frequently 
is  localized  in  a  very  circumscribed  spot,  as  in 
tetanus  and  in  diphtheria. 

The  idea  of  intoxication  by  these  products  has 
now  replaced  the  idea  of  the  direct  action  of  the 


*  Roux   and  Yersin;    Memoire  sur  Diphterie.     Ann.  Inst. 
Pasteur,  1 888-1 889. 


TOXINS   AND   ANTITOXINS.  *7 

microbe  on  the  elements  or  the  liquids  of  the  organ- 
ism. 

The  occurrence  that  takes  place  in  diphtheria 
and  tetanus  is  one  of  the  best  examples  to  cite  in 
support  of  this  view. 

Here,  in  fact,  the  pathogenic  microbe  is  found 
only  in  a  very  limited  area  in  the  organism  attacked 
— the  false  membrane,  in  the  case  of  diphtheria,  <»r 
frequently  only  a  slight  wound  in  the  case  of 
tetanus,  and  the  microbe  becomes  localized  there 
only.  Now,  in  both  cases,  there  are  general 
phenomena  of  toxic  effects.  There  must  hence  be 
a  diffusion  of  toxic  substances  which,  distributed 
by  the  blood,  affect  the  different  systems  and 
exert  a  toxic  action  on  the  entire  organism. 

It  must  be  observed  that  the  toxins  act  as  toxic 
agents  only  when  in  a  condition  to  be  intro- 
duced into  the  circulation  subcutaneously.  The 
cause  of  this  innocuousness  of  the  toxins  when 
given  per  os  has  frequently  been  studied.  It 
appears  to  be  quite  probable  that  the  cause  of 
the  attenuation  of  the  morbid  properties  is  due 
to  the  interveniton  of  the  digestive  microbes. 
Such  is  the  opinion  of  Levaditi  and  Charrin  * ;  it 
is  also  the  conclusion  that  is  to  be  drawn  from  the 
experiments    of    Mme.    Metchnikoff    and    of    Cal- 

*  Charrin  and  Levaditi:  Lc  sort  de  toxines  introduites  dans 
le  tube  digestif.  Journal  dc  Physiologic  el  dc  Pathologie Generates, 
iSyS,  p.  226. 


1 8  TOXINS  AND   ANTITOXINS. 

mette  *  on  the  modifications  undergone  by  a 
vegetable  toxalbumin,  abrin,  and  by  serpent 
venoms,  when  these  toxalbumins  are  inoculated 
with  the  bacillus  subtilis  chromogenus.  Moreover, 
Charrin  and  Lefevre.f  on  the  one  hand,  and 
Nencki,  Sieber  and  Somanowsky,t  and  Carriere,§ 
on  the  other  hand,  have  discovered  that  the  diges- 
tive ferments,  particularly  trypsin,  destroy,  even 
though  but  little,  the  toxins  secreted  by  the  Loeffler 
and  Nicolaier  bacilli.  This  is  practically  contrary 
to  the  opinion  of  Behring  and  of  RausonJI  according 
to  which  the  innocuousness  of  the  microbial  poisons 
when  administered  per  os  is  due  exclusively  to  the 
lack  of  absorption. 

Nature  of  the  Toxins. — The  molecules  of  the  toxins 
are  very  nearly  like  those  of  the  diastases.  Like 
these,  the  toxins  appear  to  have  a  very  complex, 
and  very  unstable,  internal  structure.  Their  mode 
of  action  frequently  depends,  as  in  the  case  of  the 
diastases,  upon  the  medium  in  which  they  occur. 
Again,  like  the  diastases,  they  are  generally  de- 
stroyed by  the  action  of  sufficiently  prolonged  heat, 
but  less  easily,  for  there  are  certain  toxins  that 
resist  a  temperature  of  ioo°  C.  for  an  indefinite 
period.     They  are,  like  the  diastatic  albuminoids, 

*  Citing  Metchnikoff. 

t  C.  rend,  de  la  Soc.  de  Biologie,  1898. 

%  Centralblatt  fur  Bakt.,  1898. 

§  C.  rend,  de  la  Soc.  de  Biologie,  1899. 

||  Deutsche  Med.  Wochenschr.,  1898,  No.  8. 


TOXINS    AND    ANTITOXINS.  Iy 

insoluble  in  strong  alcohol,  and  are  precipil 
from  their  solutions  on  the  addition  of  this  reagent. 
They  easily  adhere  to  precipitates  that  form  in 
liquids  in  which  they  occur  in  solution,  and  possess 
the  remarkable  property  of  diastases  in  that  impon- 
derable  masses  produce  considerable  results.* 

Although  closely  allied  to  certain  alkaloidal  bases, 
the  toxins  are  sharply  distinguished  by  the  remark- 
able fact  that  their  action  is  never  immediate,  but 
is  always  preceded  by  a  period  of  incubation,  which 
may  be  quite  long. 

Like  the  alkaloidal  bases,  they  appear  to  result 
from  the  hydrolyzing  breaking  down  of  albu- 
minoids and  nucleo-albumins,  and  they  appear  to 
be  intermediary,  from  a  chemical  point  of  view, 
between  these  bodies,  the  general  characters  of 
which  they  retain,  and  the  alkaloids  proper,  or 
ptomaines,  to  which  we  have  called  attention,  and 
the  principal  chemical  and  physiological  properties 
of  which  they  possess. 

No  absolutely  precise  knowledge  is  had  regard- 
ing the  chemical  nature  and  constitution  of  these 
remarkable  substances.  A  number  of  analyses  of 
these  substances  have  been  published  which,  in 
general,  permit  no  definite  conclusion  to  be  drawn. f 


*  See  Tozzi -Escot:  Lcs  diastases  et  leurs  applications,  pub- 
lished by  Masson.  1900;   and  Traiie  de  Physico-ckimie. 

f  Regarding  this  see  the  works  by  Koch  and  Brieger, 
Deutsche  Medicin.  Wochenschr.,  Oct.  22,  1S91. 


26  TOXINS   AND  ANTITOXINS. 

I  have,  however,  elaborated  several  speculative 
ideas  regarding  this  subject.* 

We  must  here  call  particular  attention  to  the 
ideas  of  Ehrlich  regarding  the  constitution  of  the 
toxins.  According  to  this  scientist,  their  molecules 
contain  two  functional  groups;  the  one,  to  which 
he  has  given  the  name  "  haptophore,"  is  that 
which  enables  the  toxin  to  attach  itself  to  any 
cellular  element  whatever,  and  which  it  then 
renders  non-toxic  by  means  of  the  other,  or  ' '  toxo- 
phore,"  group.  We  will  particularize  farther  on 
regarding  this  very  important  conception. 

Origin  of  the  Toxins. — These  toxic  bodies  result 
either  as  the  products  of  the  secretion  of  microbial 
life,  or  as  the  result  of  the  normal  functionation  of 
cellular  life  in  the  higher  vegetable  or  animal 
organisms. 

They  are  the  direct  products  of  life,  and  do 
not  result,  as  was  formerly  believed,  from  a  more 
or  less  profound  modification  of  the  more  or  less 
complex  albuminoids  that  serve  as  a  food  for  the 
various  species  of  microbes,  or  for  the  cellular  ele- 
ments. 

The   vegetable   toxins   are   less   numerous   than 

*  Pozzi-Escot:  Nature  des  Diastases.  Published  by  J. 
Rousset,  Paris,  1903.  See  also  Recherches  de  la  Nature  Chi- 
mique  des  Diastases  Oxydantes.  Revue  gene'r.  de  chimie,  vu,  pp. 
129—136;  and  Apercus  sur  la  nature  chimique  des  Diastases, 
Bulletin  de  V Association  de  Chimistes ,  1904,  p.  769. — Proprietes 
Catalytiques  de  Quelques  Diastases;   Ibid.,  1904,  p.  1247. 


TOXINS    AND   ANTITOXINS.  21 

the  animal  toxins.  They  are  met  with,  never- 
theless, in  almost  all  mushrooms  which  are  reputed 
or  known  to  be  toxic;  the  seed  of  the  castor  plant 
contains  a  very  toxic  vegetable  albuminoid,  as  is 
likewise  the  case  with  Abrus  prccatorius  (jequirity- 
bean),  and  certain  others. 

The  true  physiological  toxins  occupy  a  very 
important  place  in  the  realization  of  the  condi- 
tions that  govern  health,  sickness,  and  death. 

We  will  see  later  on  that  they  are  met  with  in 
quite  large  number  in  the  bladder,  whence  they 
are  voided  in  the  urine.  Their  number  varies  con- 
siderably, according  to  diverse  influences  (waking, 
slumber,  eating,  fasting,  fatigue,  oxygen,  brain- 
work,  health,  disease,  etc.).  It  is  necessary  here  to 
observe  that  the  renal  system  serves  for  the  puri- 
fication of  the  entire  organism,  and  that  in  the 
case  of  normal  life  we  will  find  in  the  renal  system 
a  large  portion  of  the  products  of  the  cellular  secre- 
tion of  the  organism,  and  among  the  number  there 
are  found,  as  we  know,  a  certain  number  of  alka- 
loidal  bases.  We  will  take  up  later  the  subject  of 
urinary  toxicity. 

Autointoxications. — The  toxins  are  also  en- 
countered, and  often  in  some  number,  in  the  mus- 
cular tissues  and  in  the  blood,  particularly  in  those 
of  batrachians,  mureids,  and  saurians.  In  the 
organism  these  toxins,  developed  by  the  activity 
of   the   various   cells,    may   cause   autointoxication 


22  TOXINS   AND    ANTITOXINS. 

whenever,  for  one  cause  or  another,  their  nor- 
mal elimination  ceases.  "Although  there  are  an 
infinity  of  diseases,"  remarked  Prof.  Bouchard, 
"  there  are  but  a  few  ways  of  becoming  ill."  Of 
these  ways  that  of  autointoxication  is  the  most 
frequent.  "  What  else  is  it,  then,"  says  Prof. 
Charrin,  "  in  the  last  analysis,  but  to  die  from 
affections  of  the  kidney,  the  liver,  the  heart,  the 
lung,  etc.,  if  it  be  not  to  succumb  because  of  the 
lack  of  oxygen,  the  accumulation  of  carbonic  acid, 
the  influence  of  the  numerous  urinary  poisons, 
the  action  of  acids,  of  salts,  of  biliary  pigments,  or 
the  effect  of  noxious  principles,  which  the  hepatic 
cell  must  norma1  ly  destroy  or  at  least  attenuate." 

These  autointoxications,  always  due  to  poor 
elimination  of  toxic  principles,  toxins  formed  in 
very  great  number  in  the  organism,  and  which 
the  normal  modes  of  evacuation  or  destruction  do 
not  eliminate,  are  always  found  to  be  the  cause 
of  all  diseases,  even  those  that  are  manifested  by 
attacks  of  the  cerebro-spinal  axis,  and  that  exhibit 
variously  mania,  insanity,  symptoms  of  hyper- 
excitability,  etc. 

These  autointoxications  are  controlled  by  the 
nervous  system,  and  the  latter  alone  is  the  cause 
of  a  larger  number  of  maladies  than  is  generally 
believed;  in  fact,  if  the  mechanism  of  nutrition  be 
reduced  to  its  most  simple  elements,  it  will  be 
seen  to  consist  of  the  penetration  of  the  foods,  of 


TOXINS    AND    ANTITOXINS.  23 

the  plasmatic  principles,  to  the  cells;  of  their 
transformation  within  the  interior  of  the  cells, 
and  finally  the  rejection  of  all  the  matter  that 
could  not  be  utilized.  It  is  the  nervous  system 
that  commands  or  dominates  this  mechanism,  that 
controls  the  taking-up  of  assimilable  elements  and 
the  elimination  of  toxic  principles,  the  fruit  of 
assimilation  or  disassimilation,  and  in  such  a  man- 
ner, in  fact,  that  this  same  nervous  system  can, 
at  its  will,  cause  starvation,  or  intoxicate. 

The  marvelous  cures  obtained  by  magnetic 
methods  are  due  to  no  other  causes  than  favor- 
able changes  in  the  nervous  system. 

General  Mode  of  Action. — The  toxins,  of  whatever 
kind,  always  behave  like  diastases,  in  the  sense 
that  their  definite  action  appears  to  be  absolutely 
independent  of  their  mass,  and  that  imponderable 
quantities  suffice  to  cause  serious  morbid  affections 
and  profound  modifications  in  nutrition. 

Koch  has  shown  that  tuberculin  is  capable  of  affect- 
ing 60  trillion  times  its  weight  of  the  living  human 
being.  According  to  Vaillard  one  milligramme  of 
tetanus  toxin  will  kill  a  horse  weighing  600  kilos. 
These  two  examples  show  what  an  enormous  power 
the  toxins  possess. 

My  views  regarding  the  manner  in  which  dias- 
tases act  I  have  developed  at  length  in  my  work 
Nature  des  Diastases.  The  close  analogy  between 
these  substances  and  the  toxins,  an  analogy  upon 


24  TOXINS   AND   ANTITOXINS. 

which,  moreover,  I  have  dwelt  at  some  length,  per- 
mits me  to  refer  the  reader  who  is  desirous  of  fuller 
details  to  the  small  work  just  mentioned. 

The  mode  of  action  of  diastases  resembles  sin- 
gularly closely  that  of  the  catalytic  substances, 
and  we  will  admit,  for  the  moment,  that  they 
act  by  intermediary  combination,  resulting  in  their 
rapid  decomposition. 

We  owe  to  Ehrlich  *  a  new  conception  relative 
to  the  nature  and  mode  of  action  of  the  diastases, 
and  which  to-day  plays  an  important  role  in  all 
our  conceptions  regarding  immunity.! 

According  to  this  scientist,  the  complex  mole- 
cule of  albuminoid  substances  is  constituted  by 
a  fixed  central  nucleus,  and  by  a  number  of  lat- 
eral chains  or  receptors,  fixed  to  this  nucleus,  which 
possess  diverse  accessory  functions,  and  which 
serve,  particularly,  for  the  nutrition  of  the  cells. 
These  receptors  have  a  great  affinity  for  the  vari- 
ous substances  necessary  for  the  support  of  the 
living  elements,  and  they  seize  upon  the  alimentary 
substances,  in  normal  life,  just  as  a  leaf  of  the 
Dioncea  seizes  a  fly  which  serves  as  its  food. 
In  these  special    conditions   the   receptors  may 

*  Ehrlich:  Klinisches  Jahrbuch,  1897,  vi.  Proceedings  of  the 
Royal  Society,  1900,  No.  482,  p.  424.  Nothnagles'  specielle  Patholo- 
gie  und  Therapie,  1901,  vm,  Schlussbetrachtungen,  p.   163. 

f  To  have  a  complete  expose  regarding  this  question,  it  will 
be  profitable  to  consult  No.  4  of  this  collection  on  Scrums 
Itnmunisants . 


TOXINS   AND   ANTITOXINS.  25 

attach  themselves  to  the  complex  molecules  i  1 
albuminoid  substances,  such  as  the  different 
toxins. 

Ehrlich  supposes,  as  we  have  already  seen,  that 
a  toxin  contains  two  special  groups — a  toxophore 
group,  which  poisons,  and  a  haptophore  group, 
which  combines  with  the  receptor.  According  to 
this  theory,  the  toxophore  group  of  a  toxin  can  act 
on  an  organism  only  when  the  haptophore  group 
of  the  toxin  encounters  a  suitable  attachment  or 
receptor. 

The  receptors  attached  to  the  living  proto- 
plasmic molecule  attract  the  toxin,  just  as  a  light- 
ning-rod attracts  the  lightning. 

It  is  hence  clearly  proved  that  the  toxigenic 
poisons  exert  their  noxious  action  on  the  cellular 
elements  of  sensitive  organisms,  by  entering  into 
combination  with  these. 

Experience  has  shown  that  they  attach  them- 
selves, in  a  most  rigorously  elective  manner,  to  the 
tissues,  and  rapidly  disappear  from  the  general 
circulation.  Numerous  facts,  clearly  established,  at- 
test the  reality  of  this  fixation  or  attachment. 

It  is  thus  that  von  Behring  and  Wernicke  * 
sought  to  ascertain  the  quantity  of  antitoxin  (we 
will  see  farther  on  that  this  name  is  given  to  those 
substances  which  neutralize  the  activity  of  toxins 

*  Von  Behring  and  Wernicke;  Zeitschrift  fur  Hygiene,  xn. 


26  TOXINS  AND  ANTITOXINS. 

under  certain  conditions)  which,  introduced  a  cer- 
tain time  after  the  introduction  of  the  poison, 
will  save  the  life  of  the  animal.  They  have  experi- 
mented with  diphtheria  toxin,  which  we  will  study 
later,  and  they  have  demonstrated  that,  if  the 
antitoxic  serum  be  introduced  immediately  after 
the  toxin,  a  dose  of  antitoxin  twice  as  large  as 
that  of  the  toxin  suffices  to  effect  a  cure. 

Eight  hours  after  the  administration  of  the  toxin 
the  dose  must  be  trebled,  while  after  thirty-six  hours 
it  is  necessary  to  have  recourse  to  a  quantity  of 
antitoxin  eight  times  as  great.  These  experiments 
show  that  the  curative  action  of  the  antitoxin  is 
so  much  the  less  the  longer  the  period  of  time 
that  has  elapsed  between  the  introduction  of  the  toxin 
and  the  antitoxin.  This  is  because  the  toxin  has 
become  so  intimately  attached  to  the  tissues  that 
the  antitoxin  introduced  has  not  the  power  to 
destroy  the  combination.  These  facts  have  been 
confirmed  by  Donitz  *  and  by  the  classic  experi- 
ments of  Decroly  and  Rousse.f 

This  is  not,  however,  the  case  with  cold-blooded 
animals,  which,  generally,  are  not  affected  by  injec- 
tions of  poisonous  toxins.     Thus  Metchnikoff  J  and 

*  Donitz:  Ueber  die  Grenzen  der  Wirksamkeit  des  Diph- 
theria Heilserums.     Deutsche  Med.  Woch.,  No.  27,  1897. 

f  Decroly  et  Rousse:  Arch.  Int.  de  Pharmacodyn.,  111  and 
VI ;   Masoin:  Arch.  Intern,  de  Pharmacodyn.,  11,  1903. 

J  Metchnikoff:  L'Immunite,  Paris,  1902;  Morgenroth : 
Zur  Kenntniss  des  Tetanus  des  Frosches.  Deutsche  Med.  Woch., 
No.  35,  1898. 


TOXINS    AND   ANTITOXINS.  27 

his  pupils  have  been  aide  to  show  that  the  toxins 
introduced  into  certain  cold-blooded  animals 
(Oryetcs  nasicorius)  may  remain  for  several  months 
without  alteration   in   their  circulation. 

If  we  consider  the  facts  of  the  theory  of  Ehrlich's 
lateral  chains,  which  we  have  mentioned,  we  arc 
led  to  well-defined  conclusions  regarding  the  mode 
of  action  of  the  toxins.  In  fact,  since  these  toxins 
exhibit  a  pronounced  chemical  affinity  for  the  tis- 
sues, and  while,  on  the  other  hand,  they  can  attach 
themselves  only  because  of  the  presence  of  certain 
functional  groups  of  the  protoplasmic  molecules, 
this  union  can  take  place  only  in  certain  specific 
centers.  This  has  been  fully  confirmed  by  experi- 
ments in  vitro. 

It  is  known,  since  the  researches  of  Ehrlich,* 
Wassermann  and  Takaki.f  Marie, J  Metchnikoff, § 
and  a  host  of  other  scientists,  that  this  fixation  is 
due  to  a  clearly  elective  property.  It  is  for  this 
reason  that  the  tetanus  toxin  fixes  itself  only  upon 
the  nervous  tissue,  and  that  in  this  action  all  passes 
as  if  the  nervous  tissue  had  been   provided  with 


*  Ehrlich:   Bcrl.  Klin.  Woch.,  No.  12,  iSqS. 

t  Wasskrmann  and  Takaki:  Berl.  Klin.  Woch.,  Med.,  p.  5, 
1898. 

\  Marie:  Sur  les  Proprietc's  Antitoxiqucs  aux  Centres  Ner- 
veux  de  V  Animal  Sain.     Ann.  Inst.  Past.,  1898,  p.  1. 

§  Mktchnikoff:  Recherches  sur  1' Influence  de  l'Organism 
sur  les  Toxines.      Ann-  In  *■  Part.,  1899,  p.  82. 


28  TOXINS   AND   ANTITOXINS. 

functional  groups  possessing  an  elective  affinity 
for  the  tetanic  poison. 

Means  of  Defense  Possessed  by  the  Organism 
against  the  Action  of  Toxins. — We  have  already  seen 
that  the  renal  organs  serve  for  the  elimination  of 
the  toxins  normally  produced  in  the  organism  by  the 
simple  play  of  its  cellular  mechanism.  Experience 
has  shown  that  the  toxins  introduced  from  with- 
out into  the  circulation  are  generally  finally  elim- 
inated, even  though  in  the  meantime  the  modifi- 
cations they  have  imprinted  on  the  economy  may 
be  transmitted  hereditarily;  and  that  their  influ- 
ence on  the  general  nutrition  and  the  normal  func- 
tionation  of  the  entire  organism  persists  even  after 
their  elimination. 

Much  has  been  said  regarding  the  elimination  of 
these  toxins  by  the  urine,  but  the  experiments  made 
by  Metin,  at  the  Institut  Pasteur,  have  shown  the 
inaccuracy  of  this  assumption,  and  it  has  been 
necessary  to  seek  another. 

It  has  been  remarked  that  oxidation  destroys 
the  toxins  in  vitro,  and  it  has  been  thought  that 
a  process  resembling  disinfection  may  well  take 
place  within  the  tissues  of  the  animal  economy, 
but  no  decision  has  been  arrived  at  regarding  the 
possible  mechanism  of  this  action,  which  some 
attribute  to  the  action  of  the  oxidizing  ferments 
of  the  organism,  or  to  the  action  of  certain  special 
cells. 


TOXINS   AND   ANTITOXINS.  29 

According  to  Poehl,  there  is  developed  as 
destroyer  a  substance  possessing  energetic  oxidiz- 
ing properties,  which  he  has  isolated  and  named 
spermine,  and  which  is  found  in  most  of  the  organic 
fluids  and  partieularly  in  the  leucocytes,  the  special 
role  of  which  we  will  presently  study. 

There  develops  still  another  cause  of  elimina- 
tion, or,  to  be  more  exact,  of  the  neutralization  of 
the  toxic  principles  in  defense  of  the  organism 
against  the  toxins,  and  that  is  the  formation  of 
antitoxins. 

It  is  well  known  that  the  term  virus  has  been 
reserved  to  designate  physiological  liquids  which 
were  characterized,  when  first  they  were  known, 
by  their  property  of  transmitting  to  an  organism 
certain  functional  affections,  but  the  true  character 
of  which  is  to  expend  their  toxicity  upon  the 
microbes  which  occur  and  are  reproduced  in  the 
organism,  or  upon  the  organized  plastidulary  granu- 
lations, as  in  the  case  of  the  rabic  virus,  the  special 
microbe  of  which  has  not  as  yet  been  isolated. 

Pasteur,  when  studying  rabies,  found  that  the 
brain  and  spinal  marrow  of  rabid  animals  contained 
the  pure  rabic  virus  in  considerable  quantity,  and 
that  every  particle  of  the  marrow  was  capable  of 
imparting  rabies  to  a  perfectly  healthy  dog.  After 
having  ascertained  this  fact,  he  found  that  he 
could  attenuate  the  action  of  the  virus,  cither  by  pass- 
ing the  virus  through  certain  animal  organisms,  such 


30  TOXINS  AND   ANTITOXINS. 

as  the  monkey  or  rabbit,  by  gently  heating,  or  even 
by  allowing  it  to  oxidize  and  partially  dry  in  the 
air,  or  else  by  submitting  it  to  the  action  of  anti- 
septics or  alternating  electric  currents  of  very  high 
tension. 

Experiments  have  shown  that  a  deadly  virus, 
attenuated  by  one  of  the  means  mentioned,  may 
be  injected,  without  danger  of  death,  into  the  living 
animal;  and  what  is  still  better,  the  animal  thus 
treated  acquires  the  power  of  resisting  large  doses 
of  the  virus,  less  and  less  attenuated,  and  that  it 
is  possible  to  reach  a  point  where  the  animal 
economy  may  become  habituated  to  very  large 
doses  of  a  highly  virulent  virus  without  the  organ- 
ism experiencing  any  visible  illness — that  is,  the 
organism  has  been  vaccinated  with  regard  to  the 
particular  virus. 

Experiments  have  shown  that  this  property  is 
not  peculiar  to  microbial  virus  alone,  but  that  it 
is  common  to  the  venoms  the  toxicity  of  which  is 
essentially  due  to  some  toxins,  with  the  exception 
of  those  agents  noted. 

The  attenuated  viruses  act,  as  vaccins,  through 
their  soluble  constituents,  which,  either  directly,  by 
modifying  the  nutrition  of  certain  cells,  or  indirectly, 
by  inducing  reactions  of  the  nervous  centers  which 
preside  over  this  nutrition,  profoundly  change  the 
conditions  of  life  and  give  rise  to  the  pathological 
condition — the  vaccined  state. 


TOXINS    AND    ANTITOXINS.  3* 

Experiments  by  Behring  and  Kitasato*  have 
shown   that  the   tumors  of  a  vaccinated   animal, 

freed  from  all  organized  matter  visible  under  the 
microscope  by  filtration  through  porcelain,  contains 
principles  capable  of  directly  or  indirectly  protect- 
ing other  animals  from  the  disease  caused,  by  the 
corresponding  virus.  Meanwhile,  experiments  have 
shown  that  the  vaccinating  matters  are  totally 
eliminated;  nevertheless,  after  their  elimination, 
the  immunity  acquired,  remains  with  the  animal, 
which  then  continues  to  be  protected  against  the 
corresponding  virus. 

Interest  in  this  subject  has  incited  numerous 
researches  with  a  regard,  to  bringing  to  light  the 
mechanism  of  this  immunization;  and  this  will 
form  the  subject  of  another  volume  of  this  collec- 
tion. We  may  state  here,  however,  that  there 
have  been  recognized  two  concurrent  causes  of 
this  preservative  action;  the  one,  called  phagocy- 
tosis, results  from  the  fact  that  the  microbe  intro- 
duced into  the  vaccined  organism  becomes  incapable 
of  producing  its  usual  toxins,  while  on  the  other 
hand  the  immunization  renders  the  organism 
capable  of  secreting  substances  possessing  an 
activity  contrary  to  that  of  the  virus,  in  fact  true 
counter-poisons,  comprised  under  the  general  name 
antitoxins. 

*  Deutsche  Med.  Wochet&chr.,  1890,  p.  1113. 


32  TOXINS   AND  ANTITOXINS. 

Phagocytosis. — We  have  seen  that  an  organism 
subjected  to  a  toxic  invasion  tends  to  protect  itself 
by  proper  means  of  defense;  and  one  of  those  is 
the  direct  putting  into  activity  of  the  living  cellular 
elements  themselves,  and  in  particular,  the  leuco- 
cytes, or  white  corpuscles,  found  in  more  or  less 
number,  according  to  pathological  conditions,  in 
the  blood  and  lymphatic  fluids.* 

Metchnikoff  has  shown  that  the  moment  a 
foreign  element,  particularly  a  microbe,  enters  the 
organism,  these  leucocytes  come  nocking  from 
all  parts  of  the  bod)7-,  collect  around  the  bacte- 
rial element,  penetrate  it,  and  begin  to  digest  it. 
These  elements  have  received  the  name  phagocytes. 
The  name  chemotaxis  has  been  given  to  the  prop- 
erty by  virtue  of  which  they  approach  (positive 
chemotaxis)  or  move  away  from  (negative  chemo- 
taxis) certain  substances  which  affect  them  power- 
fully. 

Experiments  have  shown  that  the  leucocytes 
are  attracted  by  the  products  secreted  by  patho- 
genic microbes,  or  saprophytes.  Attracted  by 
the  latter,  the  white  corpuscles  surround,  envelop, 
and  finally  digest  them;  and  when  it  happens  that 
all   the   pathogenic   microbes   within   an   organism 


*  It  is  necessary  here  to  consult  the  work  by  Levaditi: 
Le  Leucocyte  et  ses  Granulations.  Sc'entia,  Naud,  publisher, 
Paris,  1903;  also  Metchnikoff:  L'Immunite,  Paris,  1902, 
Masson,    publisher. 


TOXINS   AND    ANTITOXINS.  33 

are  absorbed,  the  organism  survives,  while  in  the 
contrary  case  it  succumbs. 

Attention  must  be  called  to  this  attack  by  the 
white  corpuscles  within  the  limits  where  they  are 
normally  confined.  It  is  a  pathologic  diapedesis — 
a  leucocytosis  provoked  by  the  irritation  of  the 
tissues — and  caused  either  by  the  presence  alone 
of  foreign  elements,  or  by  the  soluble  products 
secreted  by  them. 

When,  for  any  reason  whatever,  this  phagocytic 
action  is  impeded,  the  resistance  of  the  organism 
to  pathogenic  infection  ceases  to  be  effective, 
and  the  organism  may  therefore  be  invaded  by 
the  microbe.  Numerous  causes  may  contribute  to 
impede  this  action. 

The  Antitoxins. 

We  have  seen  that  the  second  means  of  defense 
possessed  by  the  organism  resides  in  the  action  of 
special  products,  true  defensive  secretions,  pos- 
sessing an  activity  contrary  to  that  of  the  toxins, 
and  which  are  secreted  by  the  cells  of  the  organism 
under  the  influence  of  the  vaccins. 

This  is  a  property  common  to  every  organism, 
and  which  is  observed  even  in  non-vaccinated 
subjects,  although  in  this  case  the  secretion  forms 
with  great  difficulty  and  in  small  quantity. 

When  an  organism  subjected  to  the  toxic  action 
C>f  a  bacterial    infection    does   not   succumb  to   the 


34  TOXINS  AND   ANTITOXINS. 

intoxication,  it  emerges  from  the  test  gifted  with  a 
new  property,  which  may  be  augmented  by  habitua- 
tion, and  which  borders  on  immunity. 

At  first  we  were  content  to  vaccinate  small 
animals  in  the  laboratory,  but  in  proportion  as  the 
discoveries  in  this  domain  extended,  and  there 
developed  a  need  for  large  quantities  of  antitoxins, 
recourse  was  had  to  the  larger  animals,  particularly 
horses  and  cattle.  From  the  moment  that  large 
quantities  of  blood  and  antitoxic  serum  were  at 
command,  search  was  made  for  a  means  of  isolating 
the  antitoxin  and  determining  its  properties. 

Experiments  so  far  made  have  shown  that  the 
antitoxins  are  substances  of  an  albuminoid  nature, 
of  unknown  composition,  and  which  are  very  closely 
united  to  the  albuminoid  substances  of  the  serum. 
It  must  be  observed,  however,  that  Behring  and 
Knorr  oppose  the  assertion  regarding  the  albuminoid 
nature  of  tetanic  antitoxin,  but  their  reasons  for 
this  do  not  appear  to  be  well  founded. 

In  general,  these  antitoxins  are  precipitable  with 
the  globulins,  and  possess  quite  considerable  powers 
of  resistance  towards  physical  and  chemical  agents. 
Thus  they  are  destroyed  only  at  a  temperature 
above  6 0-6  5  °  C.  Kept  in  the  dry  state,  in  the 
residue  of  evaporated  serum,  and  away  from  the 
light  and  all  oxidizing  action,  it  is  possible  to  pre- 
serve their  activity  for  a  very  long  time. 

They   are   essentially   humoral   substances;  they 


TOXINS  AND   ANTITOXINS.  35 

are  found  in  the  Mood  of  vaccinated  animals,  from 
which  may  be  obtained  antitoxic  serums  with  a 
specific  but  transient  immunity;  and  they  are  also 
found  in  the  plasmas  of  the  lymph  and  exudates, 
in  aqueous  tumors,  and  in  the  milk.  They  are 
seldom  found  in  the  cells. 

Mode  of  Action. — Frequent  attention  has  been 
paid  to  the  mode  of  action  of  the  antitoxins  upon 
the  toxins,  a  phenomenon  of  great  importance  in 
relation  to  the  phenomenon  of  immunity  acquired 
against  the  toxins.  At  the  beginning  of  our 
knowledge  on  this  subject,  the  idea  of  a  destruction 
of  the  toxin  immediately  suggested  itself,  and  was 
advanced  by  von  Behring.*  According  to  this 
scientist  the  antibody  inhibits  the  morbigenic  action 
of  the  toxin  by  neutralizing  the  toxin,  combining 
with  the  latter  to  form  a  compound  of  a  chemical 
nature  which  is  devoid  of  toxicity  and  without 
action  on  the  organism.  According  to  this  theory, 
the  influence  of  the  antitoxin  on  the  toxin  is  direct, 
and  does  not  require  the  intervention  of  the  living 
cellular  protoplasm.  Such  was  also  the  belief  of 
Prof.  Ehrlich.f 

Buchner,  a  little  later,  believed  that  the  anti- 
toxin, instead  of  acting  directly  on  the  toxin, 
exercised  a  direct  influence  on  the  living  elements 

*  Von'  Behring  and  Kitasato:    Deutsch.  med.  W oclicnschr ., 
1890,  p.  1 1 13. 
t  Ehrlich:  Klin.  Jahrb.  1897,  vi,  p.  292. 


36  TOXINS  AND  ANTITOXINS. 

of  the  organism,  preserving  them  from  intoxi- 
cation.* 

Such  was  also  the  opinion  of  Rouxf;  and  Cal- 
mette  demonstrated  that  a  mixture  of  venom  and 
of  a  non-toxic  antivenom  recovered  its  toxicity  on 
being  heated  to  68°  C,  whereby  the  antivenom 
was  destroyed  (Calmette:  he  Venin  des  Serpents, 
Paris,  1897,  p.  58);  and  Wassermann  arrived  at 
the  same  result.  J 

The  array  of  proofs  offered  by  these  scientists, 
which  we  cannot  here  enlarge  upon  without  use- 
lessly extending  our  subject,  would  tend  to  make 
one  believe,  at  first  glance,  that  the  antitoxin  does 
not  act  directly  on  the  toxin,  but  at  the  present 
time  Buchner's  theory  appears  untenable.  Numer- 
ous researches  have  proved  conclusively  that  the 
toxin  and  the  antitoxin  have  a  specific  affinity 
for  each  other,  by  virtue  of  which  these  principles 
combine  to  form  a  substance  free  from  all  toxicity, 
but  unstable,  and  which  may  be  decomposed  by 
heat  or  certain  other  factors.  § 

Some  recent  experiments  by  J.  Martin  and  Cherry 
{Proceedings  of  the  Royal  Society,  1898,  lxiii,  p. 
423)  have  clearly  brought  out  this  fact.  These 
authors  made  mixtures  of  serpent  venom  with  its 


*  Buchner:    Munchener  med.  Wochenschr.,  1893,  p.  480. 
f  Roux:   Annates  de  I'Institut  Pasteur,  1894,  viii,  p.  724. 
%  Wassermann:  Zeitscfir.  jur  Hygiene. 
§  J.  Danzsy:   Annates  de  I'Institut  Pasteur,  xvi,  p.  331. 


TOXINS  AND   ANTITOXINS.  37 

antivenom,  which  they  filtered  through  a  layer  of 
gelatin,  under  the  supposition  that,  if  the  venom 
and  its  antivenom  were  not  chemically  combined, 

the  former  alone  would  be  able  to  pass  through 
into  the  filtrate,  because  its  molecules  are  so  much 
smaller.  Martin  and  Cherry  allowed  the  venom 
and  its  antivenom  to  remain  in  contact  for  varying 
periods  before  filtering.  As  the  result  of  a  series 
of  experiments  carried  out  with  this  idea,  they 
have  demonstrated  that  the  filtrate  obtained  after 
allowing  a  few  minutes'  contact  between  the  two 
substances,  was  decidedly  toxic,  while  that  obtained 
after  a  contact  of  half  an  hour  was  absolutely  non- 
toxic. From  this  the  authors  conclude  that  the 
antitoxin  enters  into  chemical  union  with  the 
venom,  but  that  the  combination  does  not  take 
place  immediately,  and  requires  a  certain  length 
of  time  for  its  accomplishment. 

Ehrlich  and  Knorr  have  demonstrated  that  the 
neutralization  is  less  rapid  in  dilute  solutions  than 
in  concentrated  ones. 

Prof.  Svante  Arrhenius  has  completed  our  knowl- 
edge regarding  the  mode  of  combination  between 
the  toxins  and  the  antitoxins,  by  demonstrating  the 
occurrence  of  limited  reactions  analogous  to  the 
etherification  of  an  alcohol  by  an  acid,  and  in 
such  a  manner  that  there  always  exists,  in  a  mix- 
ture of  these  two  substances,  a  certain  quantity  of 
free   toxin   and   antitoxin.     This   is   an   important 


3&  TOXINS   AND   ANTITOXINS. 

modification  of  the  general  ideas  held  in  this 
respect.* 

It  appears  necessary  to  bring  here  more  clearly 
in  evidence  the  fact  that  the  antitoxin  inhibits  the 
noxious  action  of  the  toxin,  even  outside  the  living 
organism,  by  uniting  with  it  to  form  a  compound 
in  identically  the  same  manner  as  when  a  strong  base 
and  a  strong  acid  are  brought  together.  As  we  have 
seen,  all  the  conditions  of  environment  that  favor 
or  retard  the  formation  of  salts,  in  a  like  sense 
influence  the  neutralization  of  the  toxin  by  its 
antitoxin. 

Formation  of  Antitoxins. — Ehrlich's  theory  of 
side  chains,  to  which  reference  has  already  been 
made,  furnishes  us  with  an  explanation  of  the 
formation  of  the  antitoxins  in  tumors.  Let  us 
suppose  that,  in  the  organism,  a  cell  had  come 
into  contact  only  with  certain  toxic  molecules  in- 
capable of  compromising  its  life,  and  that  the  only 
result  was  the  immobilization  of  the  receptors 
which  are  united  with  the  haptophore  groups  of 
the  opposing  toxins.  It  is  known  that,  by  virtue 
of  a  property  inherent  in  all  living  organisms, 
during  the  phenomena  of  reparation,  there  is 
generally    an    overproduction    of    the    neoformed 

*  Svante  Arrhenius:  La  Physico-chimie  des  Toxines  et 
des  Antitoxines.  Conferences  de  la  Societe  chimique  de  Paris, 
May  20,  1904.  See  also  Madsen  and  Arrhenius:  Testkrift 
red  indivulsen  of  Stotens  Serum  Institut.     Copenhagen,  1902. 


TOXINS   AND   ANTITOXINS.  39 

parts.     In  tin-  case  we  here  speak  of,  as  the  recepti  irs 

fill  an  important  function  in  the  nutrition  of  the 
opposing  cellular  elements,  once  they  become  united 
with  the  toxic  haptophores,  they  become  incapable 

of  filling  their  normal  function  of  nutrition.  Under 
these  conditions  the  cells  develop  so  large  a  quantity 
of  receptors  that,  filling  the  cells,  and  not  finding 
any  more  room,  they  spread  into  the  blood  and 
other  liquids  of  the  organism. 

Under  these  conditions,  every  new  injection  of  toxin 
into  the  organism  is  absorbed  into  the  blood  where 
it  meets  with  the  free  receptors  which  possess  great 
avidity  for  the  haptophore  group  of  its  molecule, 
and  the  two  groups  immediately  unite,  before  the 
haptophore  group  of  the  toxin  has  been  able  to 
attack  and  intoxicate  a  cellular  element. 

We  thus  see  that  the  receptors  which,  when  in  a 
free  state  in  tumors,  play  the  role  of  antitoxics  or 
antitoxins,  become,  within  the  cellular  elements 
themselves,  the  vehicle  of  intoxications.  Figura- 
tively speaking,  so  long  as  these  fixators  are 
attached  to  the  molecule  of  the  living  protoplasm 
they  attract  the  toxin. 

According  to  this  ingenious  conception,  the 
formation  of  antitoxins  is  hence  absolutely  in- 
dependent of  the  action  of  the  toxophore  elements 
on  the  cellular  elements,  and  it  suffices  that  these 
possess  receptors  or  side  chains  capable  of  uniting  with 
the  haptophore  groups  of  the  toxin.     This  explains 


40  TOXINS  AND  ANTITOXINS. 

why  it  has  been  possible  to  produce  antitoxins  from 
toxins  which  have  lost  some  of  their  toxic  proper- 
ties, but  which  have  preserved  their  property  of 
uniting  with  antitoxic  substances.  Ehrlich  gives 
the  name  toxoids  to  those  modified  toxins  that 
have  lost  their  toxophore  groups,  while  the  hapto- 
phore  group,  the  producer  of  the  immunizing  sub- 
stance, is  still  preserved  intact. 

According  to  MetchnikofFs  theory,  which  is 
very  similar,  it  seems  quite  possible  that  the 
phagocytes,  thanks  to  the  facility  with  which  they 
absorb  poisons,  occupy  an  important  place  as 
producers  of  antitoxins.  It  has  not  been  possible 
so  far  to  verify  this  theory  in  our  at  present  im- 
perfect knowledge  regarding  this  subject.  The 
domain  of  immunity  has,  however,  made  brilliant 
conquests  during  these  last  few  years,  so  that  we 
should  not  despair  of  arriving  at  a  definite  solution 
before  long. 

In  the  vaccinated  animal  the  antitoxin  is  re- 
produced, and  it  is  possible  to  obtain  several 
times,  from  the  vaccinated  animals,  successive 
portions  of  antitoxic  serum.*  The  protective  power 
of  these  antitoxins  is  absolutely  marvelous.  An 
animal  accustomed  gradually  to  the  tetanic  virus 
yields  a  serum  containing  an  antitoxin  a  thousand 
times  more  active  than  the  virus. 

*  Ch.  Salmonsen  et  Th.  Madsen:  Reproduction  de  la  sub- 
stance antitoxique.  Ann.  Inst.  Pasteur,  xn,  p.  762.  Roux  et 
Vaillard:   Ibid.,  1893,  p.  83. 


TOXINS   AND   ANTITOXINS.  41 

According  to  Vaillard,  a  quintillionth  of  a  cubic 
centimeter   of   this   antitetanic   serum   suffices   to 

preserve  one  gramme  of  Living  mouse  from  the 
effects  of  a  dose  of  tetanic  serum  that  would  other- 
wise be  surely  fatal. 

In  the  animal,  the  antitoxins  are  eliminated 
mostly  by  the  fluids  of  the  body,  and  particularly 
by  the  urine.  Ehrlich  has  demonstrated  that  they 
also  pass  into  the  milk,  and  this  fact  is  confirmed 
by  a  large  number  of  observers.  It  explains  the 
immunity  acquired  by  nurslings,  and  which  is 
transmitted  by  the  milk. 

Serotherapy. — The  search  for  antitoxins  and  their 
role  in  the  etiology  of  infectious  diseases  are  funda- 
mental points  in  actual  therapy.  It  has  been  demon- 
strated that  the  serums  of  certain  vaccinated  animals 
enjoy  very  extended  antitoxic  therapeutic  properties ; 
for  instance,  the  serum  of  vaccinated  rabbits  is  an 
antivenom  towards  erysipelas ;  and  the  sterilized  cul- 
tures of  the  pneumococcus  or  of  the  Bacillus  pyo- 
cyaneus  prevents  infection  of  carbuncle  (anthrax) . 

The  antivenomous  serum  of  the  ass  immunized 
by  injections  of  increasing  doses  of  the  venom  of 
the  terrible  naja  is  a  perfect  prophylactic  and  cura- 
tive, not  only  as  regards  the  venom  of  this  serpent, 
but  also  against  that  of  the  crotalus,  trigonocephalus, 
and  viper. 

We  shall  take  up  the  study  of  sero therapeutics  in 
another  volume  of  this  collection. 


PART  II. 

THE  TOXINS  PROPER. 


CHAPTER  III. 
I.  VEGETABLE  AND  ANIMAL  TOXINS. 

The  vegetable  toxins  possess  the  characteristic 
property  of  being  innocuous,  and  of  being  almost 
completely  devoid  of  poisonousness,  when  they  are 
absorbed  by  the  intestines ;  we  can  see,  from  this, 
how  greatly  they  differ  from  the  poisons  proper.* 

The  vegetable  toxins  known  are  quite  numerous; 
nevertheless  our  knowledge  regarding  them  is  very 
incomplete.  Our  review  of  them  will  be  chiefly 
descriptive. 

Many  of  the  leguminous  plants  are  poisonous, 
either  because  of  emanations  exhaled  by  them,  or 
by  reason  of  their  alkaloids,  or  because  of  some 
toxins  contained  in  them.  We  shall  commence 
with  these. 

Abrin. — This  toxin,  which  was  studied  in   par- 


*  It  is  understood  that  the  active  principles  of  mushrooms 
are  not  comprised  under  this  definition,  but  they  will  be  studied 
under  the  next  heading. 

42 


YK<  IK/I. \HI.K    AND    ANIMAL   TOXINS.  43 

ticular  by  Warden  and  Waddell,*  then  by  Koberl  j 

and  de  Ilellin.J  is  found  in  the  fruit  of  the  Legumi- 
nosae,  Abrus  precatorius  (wild  licorice,  or  jequirity). 
Its  name  was  given  it  by  Warden  and  Waddell,  who 

discovered  both  its  toxic  nature  and  the  vegetable 
toxin;  the  toxin  is  found  only  in  the  seeds.  To 
extract  it,  the  seeds  arc  macerated  in  water,  and 
the  solution  filtered  and  precipitated  with  alcohol; 
the  precipitate  which  forms  is  collected  and  dis- 
solved in  distilled  water,  from  which  it  is  again  pre- 
cipitated by  adding  powdered  ammonium  sulphate. 
The  precipitate  is  then  collected  and  submitted 
to  dialysis  in  order  to  eliminate  the  ammonium 
sulphate.  The  abrin  so  obtained  forms  an  albu- 
minoid substance  §  stable  at  ioo°  C,  and  possessing 
rotatory  power;  it  liquefies  starch  paste,  and  is 
extremely  toxic.  One  milligramme  suffices  to  kill 
a  rabbit  within  several  hours.  It  must  be  observed, 
however,  that,  as  is  the  case  with  all  the  toxins, 
abrin  acts  or  kills  only  after  a  period  of  incubation 
which  generally  exceeds  twenty -four  hours. 

It  is  possible  to  vaccinate  an  organism  so  as  to 
withstand  a  lethal  dose  of  abrin,  but  it  requires 
quite  a  long  time;    it  is  effected  by  injecting  into 

*  Warden  and  Waddell:  Xon-bacillar  Nature  of  Abrus  Poison. 
Calcutta,  1884. 

f  Robert:  Arbeit,  aus dent  Pkarmak.  Instiiut.     Dorpat,  1S93. 

X  Hellim:   Inaug.  Dissert.     Dorpat,  1891. 

§Eiirlich:  Experiment.  Untersuchungcn  iiber  Immunitat. 
Deutsch.  Med.  Woch.,  1S91. 


44  TOXINS    AND  ANTITOXINS. 

a  suitable  animal  very  small  doses  of  the  substance, 
and  increasing  the  quantity  gradually.  Rabbits 
which  have  been  rendered  highly  immune  towards 
venoms  are  capable  of  resisting  without  incon- 
venience doses  of  abrin  which  are  ordinarily  fatal; 
and  the  blood  serum  afforded  by  them  contains  a 
specific  antibody  for  the  substance. 

Ricin. — This  vegetable  toxalbumin  has  been 
studied  particularly  by  Stillmark,*  by  Dixon, f 
and  Thuson.J  It  is  found  in  the  seeds  of  the 
castor  plant;  three  or  four  of  the  seeds  suffice  to 
cause  a  gastroenteritis  accompanied  by  serious 
symptoms  and  even  by  death. 

It  was  first  isolated  by  P.  Ehrlich,  by  treating 
the  seeds  with  lukewarm  water,  and  precipitating 
the  aqueous  solution  with  alcohol.  The  toxalbumin 
is  soluble  in  water,  but  on  boiling  the  solution,  the 
substance  loses  in  great  measure  its  activity. 

Ricin  possesses  considerable  activity.  0.00003  Gm. 
suffice  to  kill  a  rabbit  when  injected  hypodermically ; 
0.2  Gm.  are  fatal  to  man.  The  action  is  not  imme- 
diate, but  follows  a  period  of  incubation.  Ehrlich 
has  shown  that,  exercising  precaution,  it  is  possible 
to  create,  as  with  abrin,  a  condition  of  tolerance 
or  habituation,  and  in  consequence  to  cause  the 
formation  of  a  specific  antibody. 

*  Stillmark:   Arbeit,  aus  dem  Pharmacol.  Inst.  Dorpat,  1889. 

t  Dixon:    Austr.  Med.  Gazette,  1887. 

I  Thuson:   Journ.  f.  prakt.  Chem.,  xciv,  p.  444. 


VEGETABLE   AND   ANIMAL  TOXINS.  45 

Robin. — This  toxic  albuminoid  was  obtained 
from  the  bark  of  an  Acacia  (Robinia  Pseudacacia) 
by  Power  and  Cambier,*  l>v  exhausting  with  water 
at  a  temperature  of  about  300  C,  and  precipitating 
the  infusion  with  alcohol.  The  substance  is  analo- 
gous to  ricin,  and  like  this,  possesses  powerful 
toxic  properties. 

Toxicity  of  the  Vegetable  Diastases.  The  dias- 
tases, which  have  been  treated  of  in  a  volume  of 
the  Encyclopedic  L6aute\f  and  to  which  we  would 
refer  the  reader  who  is  desirous  of  more  complete 
details,  develop  powerfully  energetic  toxic  properties 
when  injected  into  the  organism.  Thus  amylase 
causes,  when  injected  subcutaneously,  a  consider- 
able rise  of  temperature,  but  without  any  other 
toxic  symptoms.  Invertin  or  sucrasc  was  studied 
by  Roussy  under  the  name  pyretogenin,  but  it 
appears  probable  that  this  diastase  was  not  the 
only  substance  present  in  the  product,  but  that 
there  were  present  reducing  diastases,  as  we  have 
already  shown  in  the  first  volmue  of  this  collection, 
devoted  to  the  phenomena  of  reduction  within  the 
living  organism. 

The  pyretogenin  of  Roussy  gives  rise  to  an 
attack  of  violent  fever,  but  it  loses  all  activity  when 
heated  to  80-1000  C. 

*  Power  and  Cambier:    Phartn.  Journ.  and  Transact.,  1890. 

t  Pozzi-Escot;  Lcs  Diastases  et  lairs  Applications.  Masson, 
1900, 


46  TOXINS   AND   ANTITOXINS. 

Through  his  researches,  Roussy  clearly  demon- 
strated,* for  the  first  time,  that  the  fever  may 
cause  the  formation  within  the  blood  of  a  sub- 
stance clearly  belonging  to  the  class  of  soluble 
ferments  or  zymases.  Now,  it  is  well  known  that 
within  the  animal  economy  there  exist  many  fer- 
ments of  this  character ;  and  experiment  has  shown 
that  they  can,  at  a  given  period  and  under  various 
influences,  leave  the  cells  in  which  they  are  nor- 
mally localized,  pass  into  the  blood  plasma,  and 
reach  the  nervous  centers,  where  they  cause  seri- 
ous effects.  We  have  already  dwelt  upon  the 
mechanism  of  autointoxication  of  the  organism. 
The  toxic  action  of  certain  digestive  diastases  has 
been  shown  by  Hildebrandt,  who  has  demonstrated 
that  o.i  Gm.  of  pepsin  is  capable  of  killing  a 
rabbit  in  two  or  three  days. 


II.  TOXINS   FROM   MUSHROOMS. 

Mushrooms  are  alimentary  substances  of  the 
highest  order,  causing  a  general  stimulation  of  the 
entire  organism.  The  substances  met  with  belong, 
according  to  their  composition,  to  different  classes — 
celluloses,  sugars,  and  amylaceous  substances,  alco- 
hols,  acids,   fats,   astringents,   essential  oils,   resins, 


*  Roussy:    Apergu  historique  sur  les  ferments  et  fermentations, 
Paris,   1901.     J.  Rousset,  publ. 


Toxins    FROM    MUSHROOMS.  47 

alkaloids,  and  albuminoids.  The  study  of  the  last 
only,  the  albuminoids  and  diastases,  interests  us 
here.  The  most  important  of  these  albuminoid 
substances,  phallin,  was  discovered  in  1890  by 
Kobert.  Pouchet  also  has  isolated  a  whole  series 
of  other  toxic  albuminoids,  particularly  from  Ama- 
nita muscaria  (Fly  Agaric). 

There  are  alimentary  as  well  as  toxic  species  in 
every  possible  variety  among  mushrooms,  some 
species  consisting  chiefly  of  the  edible  kind,  others 
consisting  of  the  poisonous  variety. 

In  consequence  of  the  toxicity  of  mushrooms, 
great  attention  must  be  given  to  the  treatment  to 
which  they  are  subjected  when  it  is  desired  to 
utilize  them  for  alimentary  purposes.  Thus  the 
to  >xic  principles  of  several  varieties  can  be  removed, 
and  the  mushrooms  rendered  edible  by  very  simple 
means. 

Pouchet  has  made  a  very  ingenious  comparison 
between  the  ethereal,  alcoholic,  saline,  and  aqueous 
extracts  of  mushrooms,  and  bacterial  cultures.  The 
analogy  is  striking  as  to  the  presence  of  toxin, 
ti  »xalbumose,  and  albumoses  more  or  less  toxic ; 
it  is  moreover  not  exaggerated,  since,  according  to 
the  classification  generally  admitted,  mushrooms 
are  nothing  more  than  the  very  advanced  represen- 
tatives of  a  group  the  more  simple  members  of 
which  constitute  the  bacteria. 

The  same  author  has  shown  that  phallin  obtained 


48  TOXINS   AND  ANTITOXINS. 

from  the  juice  of  the  Fly  Agaric  will  kill  a  guinea- 
pig  weighing  600  grammes  in  one  hour. 

As  we  have  already  stated,  it  is  the  phalline  to 
which  the  ordinary  disorders  which  mushrooms 
cause  are  due.  According  to  Kobert,  a  1:250000 
solution  of  this  substance  causes  an  intense  hemol- 
ysis, with  all  its  disastrous  consequences. 

According  to  Pouchet,  the  flesh  of  mushrooms 
must  be  compared  with  meat  that  has  been  kept 
for  some  time  to  become  tender,  and  it  is  well 
known  that  though  this  "  tendering  "  process 
renders  the  meat  more  digestible,  it  may  also  allow 
the  meat  to  acquire  noxious  properties,  due  to  the 
presence  of  toxins. 

Phallin  is  the  type  of  those  toxic  albuminoids 
of  unknown  composition  which  exist  in  mush- 
rooms, and  which  are  comprised  under  the  name 
sapotoxins.  The  intravenous  injection  of  phallin 
into  an  animal,  in  the  proportion  of  1  part  to 
1  000  000  parts  of  body  weight,  causes  sudden 
death  within  one  minute;  in  the  proportion  of 
1:5000000,  death  occurs  in  about  three  minutes; 
in  the  proportion  of  1 :  50  000  000,  death  also  occurs, 
but  is  greatly  retarded.  An  injection  of  0.0005  Gm. 
per  kilo  of  body  weight  of  animal  causes  solution 
of  the  blood  corpuscles  to  such  an  extent  that 
thirty  minutes  later  the  blood  serum  is  strongly 
colored  red,   as  well  as  the  veins. 

Instead. of  being  easily  altered  under  the  influ- 


TOXINS  FROM    MUSHROOMS.  49 

cnce  of  an  elevated  temperature,  as  arc  many  of 
the  albuminoid  substances,  whereby  their  toxic 
power  is  lost,  phallin  may  be  boiled  for  half  an 
hour  with  water  without  undergoing  any  noticeable 

alteration.  Pellegrini  has  observed  that  the  dried 
juice  of  Amanita  Phalloides  (Death-cup)  preserves 
its  properties  for  more  than  a  year. 

According  to  a  recent  paper  by  Gillot,  the  symp- 
toms of  poisoning  by  mushrooms  must  be  ascribed 
to  albuminoids  (phallin  and  albumose),  alkaloids 
(muscarine,  choline,  or  betaine),  or  to  resinoids 
(cambogic  and  agaricic  acids). 

The  alkaloids  found  in  mushrooms  arc:  Muscari- 
dine  (an  oxyneurine),  which  possesses  considerable 
toxicity,  and  of  which  0.00005  Gm.  suffices  to  kill 
a  frog;  ncurinc  (trimethylethylammonium  hydrox- 
ide) ;  choline  (trimethyloxyethylammonium  hydrox- 
ide) ;  mycetomuscartne ;  anhydromuscarinc  (an  oxy- 
neurine) ;   and  a  whole  series  of  various  betaines. 

Symptomology. — It  is  quite  natural  to  divide 
this  symptomology  into  three  different  periods; 
that  of  incubation,  that  of  manifestation  of  symp- 
toms, and  that  of  termination. 

The  duration  of  the  first  period,  that  of  incu- 
bation, is  exceedingly  variable;  it  very  rarely 
lasts  more  than  forty-eight  hours,  and  becomes 
general  only  a  few  hours  after  absorption.  Certain 
conditions  influence  the  duration ;  firstly  the  quan- 
tity of  mushrooms  ingested,   then  the  manner  in 


50  TOXINS   AND  ANTITOXINS. 

which  they  were  prepared;  and,  to  some  extent, 
the  nature  of  the  organism,  whether  child  or  adult, 
healthy  or  in  poor  health. 

When  it  is  a  question  of  the  more  particularly 
alkaloid-containing  mushrooms,  especially  when  the 
poisoning  is  due  to  muscarine,  the  toxic  symptoms 
generally  develop  rapidly,  the  first  symptoms 
appearing  about  one  hour  after  the  ingestion  of  the 
mushrooms.  On  the  other  hand,  if  the  poisoning 
is  due  to  one  of  the  albuminoid  group,  and  particu- 
larly in  the  case  of  phallin,  the  period  of  incuba- 
tion is  longer,  and  may  last  ten,  twenty,  thirty, 
or  even  forty-eight  hours  and  more. 

The  symptoms  begin  with  dizziness  and  an 
indefinable  sensation  of  being  ill. 

The  second  period  is  characterized  chiefly  by 
digestive  and  by  nervous  derangements.  The  diges- 
tive derangements  are  evidenced  by  very  violent 
and  painful  vomiting,  and  diarrheas  of  choleraic  or 
dysenteric  character.  The  nervous  derangements 
vary  according  to  whether  they  are  developed  by 
an  alkaloid,  which  causes  delirium  with  hallucina- 
tion, or  by  albuminoids,  which  cause  depression, 
ataxo-adynamia,  and  stupor,  these  being  particu- 
larly characteristic  of  the  action  of  the  toxic  albu- 
minoids. 

As  for  the  period  of  termination,  it  results  either 
in  death  or  a  cure.  If  the  poisoning  is  due  to  phal- 
lin, death  appears  to  be  an  almost  inevitable  con-- 


TOXIN'S    I  ROM    MUSHROOMS.  5 1 

sequence,  as  it  occurs  in  So  per  cent,  or  more  of  the 
cases.  The  poisoning  l>y  the  alkaloids  is  k-ss  dan- 
gerous, and  the  cure,  when  it  does  occur,  is  very 
rapid,  almost  immediate,  in  fact,  while  in  the  case 
of  the  toxic  albuminoids  the  cure  is  very  slow,  and 
attended  by  relapses. 

One  characteristic  of  these  toxalbumins  is  that 
they  are  apt  to  develop  specific  antitoxalbumins. 
This  fact  has  been  verified  not  only  in  the  case  of 
abrin,  ricin,  robin,  and  their  analogues,  but  also 
in  that  of  the  vegetable  and  animal  diastases  possess- 
ing toxic  properties  even  in  the  slightest  degree 
only.  These  antibodies  generally  exhibit  their 
action  in  vitro.  Thus  antiricin  exerts  its  anti- 
agglutinative  action  on  the  erythrocytes  in  vitro 
in  a  saline  medium  in  which  the  erythrocytes  cannot 
live. 

Here,  again,  as  in  the  case  of  the  antitoxins,  it 
must  be  admitted  that  the  antitoxalbumin  possesses 
a  specific  affinity  by  virtue  of  which  it  unites 
chemically  with  the  toxalbumin  to  give  rise  to  a 
new  substance  which  is  devoid  of  toxicity. 

The  first  antidiastase  obtained  by  immunization 
methods,  and  according  to  the  mechanism  we  have 
already  seen,  was  antiemulsin,  obtained  by  Hilde- 
brandt.*     This    antiemulsin    counteracts,  both    in 


*  IIildebrandt:     Weitcres   ubcr    hydrolyt.    Fermcnte,    etc. 
Virch.  Arch.,  cxxxi,  1895,  p.  5. 


$  2  TOXINS   AND   ANTITOXINS. 

vivo  and  in  vitro,  the  specific  action  of  emulsin. 
These  studies  have  been  followed  by  a  large  number 
of  scientists,  particularly  by  Camus  and  Gley,* 
Carnot,  Mesnil,f  and  Charron  and  Levaditi,J  in  the 
case  of  trypsin ;  and  Sachs  §  in  the  case  of  animal 
pepsin.  Gessard  ||  obtained  a  very  active  anti- 
tyrosinase,  and  Mohl  an  antiurease. 

The  most  important  researches  regarding  this 
subject  have  been  published  by  Morgenroth,  Briot,^[ 
and  Korschum**  on  antilab  (or  antirennet).  The 
researches  of  these  authors  have  fully  demonstrated 
that  there  is  considerable  difference  between  the 
various  rennets,  which  had  heretofore  been  con- 
founded under  one  head ;  thus  there  is  no  difference 
whatever  between  animal  rennet  and  the  rennet 
extracted  by  Rosetti  ft  from  Cynara  cardunculus 
(cardoon)  so  far  as  their  coagulant  action  on  milk 
is  concerned,  yet  each  yields  an  antibody  which 
is  strictly  specific  to  itself.     From  a  scientific  point 

*  Camus  and  Gley:  Compt.  rend,  de  la  Soc.  de  Biolog., 
1897. 

f  Mesnil:  Stir  la  digestion  des  actinies.  Annates  de  I'Institut 
Pasteur,  1901. 

%  Charrin  and  Levaditi:  Compt.  rend,  de  VAcadtmie  dest 
Sciences,  1900. 

§  Sachs:    Ueber  Antiseptika.    Zeitschr.  f.  Biolog.,  1901,  xxvi. 

|]  Gessard:  Annates  de  I'Institut  Pasteur,  1901,  p.  609;  Comp. 
rend,  de  la  Societe  de  Biologie,  May,  1902. 

^f  Briot:   These  de  Doctorat  es-Sciences,  Paris,  1900. 

**  Korschum:   Zeitschr.  f.  physiolog.  Chemie,  1902,  xxxi. 

tt  Rosetti:  L'Orosi,  giorn.  di  chemica,  jarmacia  et  scienza 
affini,  1898. 


ANIMAL  TOXINS.  S3 

of  view  we  see,  therefore,  that  the  preparation  of 

antidiastases    permits    us    to    differentiate    certain 
diastases  that  could  otherwise  not  be  differentiated. 


III.  ANIMAL  TOXINS. 

As  we  have  shown  at  the  beginning  of  this  chapter, 
certain  diastases,  and  particularly  those  that  are 
concerned  with  the  digestive  processes,  pepsin, 
trypsin,  etc.,  and  which  are  produced  in  abundance 
by  the  entire  living  organism,  possess  quite  clearly 
defined  toxic  properties,  and  sometimes  to  even  a 
considerable  extent.* 

Hemialbumose,  from  which  peptones  are  formed, 
is  itself  a  dangerous  toxin.  It  is  generally  believed 
that  the  toxic  action  of  the  peptones  and  of  the 
products  of  digestion  of  the  albuminoids  is  due  not 
to  the  peptone  itself,  but  to  the  more  advanced 
products  of  digestion,  alkaloidal  products  unques- 
tionably closely  allied  to  the  ptomaines. 

Nevertheless,  the  true  peptones  behave  just 
like  true  poisons,  when  they  are  introduced  hypo- 
dermically  into  the  blood. f 

Brieger  has  made  us  acquainted  with  a  non- 
pro  teid  substance,  under  the  name  of  "  peptotoxin," 
which  is  met  with  at  the  beginning  of  the  putre- 

*  Glstave  Saux:    De  la  toxicite  des  produits  de  la  digestion 
peptique.     These  de  doctorat,  Bordeaux,   1902. 
f  Schmidt:    Muhlheim,  Arch,  de  physiol.,  1SS0. 


54  TOXINS   AND   ANTITOXINS. 

faction  of  albuminoids.  This  toxin,  which  is  not  a 
protein,  is  nothing  else  but  a  ptomaine.  It  is  not 
altered  by  heat,  and  possesses  a  very  high  toxicity. 
Brieger  claims  that  it  is  a  hydroxylized  derivative 
of  an  aromatic  amide.* 

Besides  these  facts,  experiment  has  shown  that 
the  leucocytes,  or  white  corpuscles,  the  defensive 
role  of  which  we  have  noted  in  phagocytosis,  owe 
their  properties  to  the  ferments  which  they  secrete, 
and  particularly  to  some  of  the  digestive  ferments. 
These  white  corpuscles  are  very  rich  in  ferments 
of  all  kinds.  Rossbach  found  in  them  amylase; 
Achalme  found  lipase,  casease,  and  trypsin;  and 
the  study  of  immunity  has  brought  to  light  a 
series  of  other  ferments,  the  alexins  or  cytases 
(microcytase  and  macrocytase) ,  which  have  an 
exceedingly  important  role  to  play. 

It  may  easily  be  conceived  that  under  certain 
circumstances  a  part  or  the  whole  of  these  ferments 
can  pass  into  the  blood  of  the  fluids  of  the  body, 
when  they  give  rise  to  serious  disturbances  in 
certain  cases,  or  confer  immunity  in  others. 

It  is  thus  that,  according  to  Gautier,  the  rise  of 
temperature  which  characterizes  fever  is  a  conse- 
quence of  the  abnormal  transudation  of  these 
normal  ferments  into  the  blood,  and  their  trans- 


*  Brieger:    Berichte  d.  D.  chem.  Gesellsch.,  xix,  p.  3120;  and 
Verhandl.  d.  Congress  f.  inner e  Med.,  11,  p.  277. 


ANIMAL  TOXINS.  55 

mission  by  the  general  circulation  to  the  nervous 
centers. 

However,  it  is  not  only  in  the  leucocytes  that 
we  meet  with  these  toxic  digestive  ferments;  it 
appears  quite  probable,  and  has  even  been  partially 
demonstrated,  that  they  occur  in  a  large  number  of 
other  cellular  elements. 

It  is  not  necessary  here  to  dwell  upon  the  forma- 
tion of  the  antibodies  of  this  group  of  active  sub- 
stances. The  animal  toxins  arc  animal  diastases, 
and  we  have  seen  in  the  preceding  paragraph  that 
these  substances  yield  specific  antibodies  with 
great  facility.  For  the  rest,  we  will  dwell  more 
fully  on  these  antibodies  of  the  animal  toxins  in 
another  volume  of  this  collection,  specially  devoted 
to  the  study  of  these  substances,  and  entitled 
ilLes  Scrums  Immunisants,"  to  which  we  refer 
the  reader  who  is  desirous  of  obtaining  more 
complete  details  than  he  can  obtain  in  the  present 
volume. 

Alimentary  Intoxications.  —  What  we  have 
already  stated  permits  us  to  understand  the 
phenomena  of  indigestion  and  botulism.  The  toxic 
substances  form  within  the  digestive  tract  when 
the  nervous  conditions  modify  the  composition  of 
the  gastric  juice,  and  arrest  the  flow  of  hydro- 
chloric acid,  the  presence  of  which  normally  checks 
the  development  of  the  microbial  flora,  so  rich 
within  the  stomach.     The  result  is  the  production, 


56  TOXINS  AND  ANTITOXINS. 

within  the  organism,  of  all  kinds  of  dangerous 
toxins.  The  same  thing  happens  when  the  liver 
does  not  functionate  normally,  and  this,  affords  us 
a  knowledge  of  the  mechanism  by  which  foods  that 
are  most  wholesome  may  become  toxic  by  reason  of 
poor  digestion  or  poor  assimilation. 

The  absorption  of  spoiled  viands  may,  a  fortiori, 
produce  serious  results.  The  alteration  may  be 
due  not  only  to  a  bacterial  infection,  as  in  tainted 
meat,  but  it  has  also  been. proved  that  the  flesh  of 
an  animal  that  has  died  of  terror  or  madness  may 
be  very  dangerous  as  a  food,  even  after  cooking, 
because,  although  there  are  toxins  which  are 
destroyed  by  a  sufficient  heat,  there  are  ptomaines 
and  certain  toxins  that  resist  destruction  under 
these  conditions.* 

The  use  of  preserved  but  spoiled  beef,  preserved 
ham  or  birds,  sausages  frequently,  and  pieces  of 
pork  tainted  by  sausage  poison,  gives  rise  to  a 
succession  of  toxic  symptoms  the  principal  ones  of 
which  are  dryness,  constriction  of  the  pharynx, 
bilious  vomiting,  diarrhea,  dyspnea  with  pulmon- 
ary edema,  etc.  Fish  and  eggs  are  foods  quite 
frequently  capable  of  developing  serious  results; 
the  same  is  the  case  with  molluscs,  mussels,  oysters, 
lobsters,  and  snails.  Lastly,  moldy  bread,  spoiled 
cheese,  putrid  water,  and  spoiled  vegetables  them- 

*  Pollin  and  Labit:  Examens  des  aliments  suspects,  Masson, 
publisher. 


.WI.MAL  TOXIN'S.  57 

selves,  are  proper  agents  for  determining  attacks  of 
botulie  poisoning. 

We  have  seen,  at  the  beginning  of  this  volume, 
that  putrid  meats  contain  ptomaines,  which  are 
among  the  most  toxic  alkaloidal  bases.  We  have 
slu  )\\  n  that  Briegcr  has  isolated  from  them  neuridinc, 
putrescine,  muscarine,  and  guanidine ;  that  Nencki 
has  isolated  hydrocollidine;  and  that  Gautier  and 
Etard  have  obtained  from  them  parvoline — only  to 
mention  a  few  of  them. 

Lastly,  there  may  develop  within  the  gastro- 
intestinal tract  dangerous  putrefactions,  the  prod- 
.  ucts  of  which  may  enter  the  veins  and  arteries  from 
the  ileum  (a  portion  of  the  small  intestine)  and  be 
distributed  throughout  the  organism.  Although 
such  poisonings  occur.,  they  do  not  immediately 
follow  the  ingestion  of  the  spoiled  or  toxic  foods, 
but  they  are  always  preceded  by  a  period  of  incu- 
bation varying  from  several  hours  to  several  days. 
These  alimentary  poisonings  are  recognized  by 
a  great  physical  depression,  accompanied  by  vomit- 
ing and  paralysis  of  the  lower  extremities,  sweats, 
and  diarrheas.  In  some  cases  there  occur  cuta- 
neous eruptions;  and  when  death  happens,  this 
occurs  only  several  days  later,  and  generally  with- 
out being  preceded  by  any  great  pain. 

Urinary  Toxins. — As  we  have  already  remarked 
several  times,  it  is  by  the  renal  way  that  the 
organism  voids  its  principal  waste  products. 


58  TOXINS  AND   ANTITOXINS 

We  have  seen  also  that  it  is  by  the  kidneys  that  the 
toxins  are  eliminated  in  all  pathological  conditions. 
As  a  general  rule,  the  urines  are  always  more  or  less 
toxic.  This  toxicity  of  the  urines  must  be  attrib- 
uted in  the  first  place  to  the  crystallizable  organic 
principles  (ptomaines  and  leucomaines  *)  which  they 
contain ;  secondly,  to  the  non-crystallizable  f  ex- 
tractive matters  not  so  well  known;  and  lastly,  to 
the  saline  substances,  among  which  the  potassium 
salts  are  the  most  active.  We  find  these  mineral 
salts  particularly  abundant  under  normal  con- 
ditions in  the  urines  of  the  herbivora.  According 
to  Bouchard,  0.18  Gm.  of  potassium  chloride  are 
sufficient  to  prove  fatal  to  1000  Gm.  of  living  organ- 
ism ;  a  man  excretes  on  the  average  2 . 5  Gm.  of  this 
salt,  and  a  rabbit  excretes  about  double  this  quan- 
tity, weight  for  weight. 

A  very  large  number  of  hypotheses  have  been 
advanced  regarding  the  toxicity  of  the  urines. 
Wilson  considers  the  urea  as  being  responsible  for 
it;  StadthagenJ  believes  it  to  be  due  to  the  potas- 
sium salts,  etc.  Bouchard  §  was  the  first  to  recog- 
nize that  the  toxicity  of  the  urines  is  due  to  a 
number  of  causes.  We  will  not  dwell  further  on 
these  active  principles  which,  in  the  last  analysis, 

*  Adduco:   Arch.  Ital.  de  biolog.,  1891. 

•j-  Pouchet:    These  de  Doctorat  en  Medecine,  Paris,  1878. 

%  Stadthagen:  Zeitschr.  f.  Klin.  Med.,  xv. 

§  Bouchard:  Lecons  sur  les  Autointoxications. 


AM  MA  I.  TOXINS.  59 

arc  no  other  than  those  that  form  in  the  various 
portions  of  the  organism,  and  which  are  eliminated 
by  the  urine. 

It  is  self-evident,  and  it  has  already  been  shown, 
that  the  toxicity  of  the  urines  varies  greatly 
according  to  the  malady,  in  consequence  of  the 
elimination  of  toxins  by  the  urines.  According 
to  Bouchard,  in  infectious  maladies  the  urines 
are  twelve  times  more  highly  charged  with  toxins 
than  is  blood  serum.  Moreover,  the  toxicity  of 
the  urines  is  considerably  augmented  the  moment 
there  is  the  least  febrile  condition,  no  matter  what 
the  cause  is.* 

Even  in  the  normal  condition,  the  urinary  toxicity 
varies  greatly ;  and  this  is  easily  conceived  since  the 
physiological  phenomena  that  control  this  secre- 
tion undergo  incessant  rise  and  fall.  Thus,  for 
example,  the  urines  eliminated  during  sleep  are 
less  active  than  those  produced  during  waking, 
because  during  sleep  the  elimination  of  cellular 
poisons  is  at  a  minimum.  Exercise,  walking, 
physical  and  intellectual  labor,  exert  their  portion 
of  influence  on  these  oscillations  of  toxicity;  and 
this  variation  of  toxicity  is  due  not  to  any  one 
variation  in  the  mineral  extractive  matters,  but 
rather  more  or  less  to  the  organic  toxic  products. 
We  will   not  dwell  further  on  this  subject,  but  will 

*  Regarding  this  point  see  the  excellent  work  by  A.  Charrin: 
Poisons  de  VQrganisnp.     Masson,  pub). 


60  TOXINS   AND  ANTITOXINS. 

simply  refer  to  the  work  by  Charrin,  already  men- 
tioned, for  all  supplementary  details. 

Autointoxications.* — The  cells  of  the  organism 
having,  as  a  whole,  a  life  very  much  like  that  of 
the  microbes,  it  is  quite  natural  that  among  the 
excreted  products  of  the  living  tissues  there  should 
be  found  the  same  substances  formed  as  a  re- 
sult of  the  anaerobic  fermentation  of  albumin- 
oids. Experiment  has  demonstrated  that  this  is  so, 
and  Armand  Gautier  has  irrefutably  proven  the 
existence  of  these  principles.!  Bouchard  was  the 
first  to  demonstrate  the  toxic  nature  of  muscle 
extract,  J  and  Roger  §  established  the  fact  that 
the  toxicity  of  this  extract  is  due  to  ferment-toxins ; 
it  has  since  been  recognized  that  after  death  these 
toxins  accumulate  in  the  muscles. 

The  extract  of  kidney  made  rapidly  by  cold 
process  by  triturating  the  washed  kidney  with 
glycerin,  and  precipitating  the  glycerinic  solution 
with  alcohol,  contains  toxic  ferments  to  which  the 
name  "  hystozymes  "  has  been  given. ||  These  fer- 
ments split  up  hippuric  acid  into  benzoic  acid  and 
glycocoll.     Lepine   has  likewise   discovered  in   the 

*  Ch.  Bouchard:   Des  Autointoxications.     Paris,  1887. 

f  Bull.  Acad,  de  Medecine  (2),  x,  p.  947,  and  xx,  p.  115. 

%  Bouchard:   Lecons  sur  les  Autointoxications,  Paris,  1887. 

§  Roger:  Toxicit6  des  Extraits  des  Tissus  Normaux.  Sec. 
de  Biolog.,  1891,  p.  728. 

||  It  is  well  to  recall  here  that  the  kidneys  contain  both 
reducing  and  oxidizing  ferments,  as  has  been  demonstrated 
by  de  Rey-Pajlhade,  and  later  by  Abelous  and  Gerard. 


ANIMAL    TOXINS.  6l 

kidney  a  very  toxic  pyrogenic  substance*  Roger 
has  given  us  evidence  of  the  toxic  properties  of 
the  liver,  washed  and  pulped,  and  then  sterilized 
by  filtration  through  a  porous  diaphragm.  This 
scientist  lias  shown  that  the  toxic  properties  are 
due  to  albuminoids,  which  lose  their  activity  when 
healed  to  ioo°  C.f 

It  must  be  remarked  that  the  organs  we  have 
studied  are  essentially  reducers,  and  that  the 
more  powerful  reducers  yield  the  most  toxic  ex- 
tracts. We  find  here  a  confirmation  of  Armand 
Gautier's  views  regarding  the  anaerobic  origin 
of  the  toxic  substances  formed  within  the  or- 
ganism. J 

Blood  serum  precipitated  by  alcohol  affords  prod- 
ucts which  possess  very  marked  toxic  power.  It 
would  appear  that  the  toxic  products  we  speak  of 
here  are  thermogenic  diastatic  substances  derived 
from  the  white  blood  corpuscles.  In  certain  diseases 
the  blood  serum  may  acquire  a  high  degree  of 
toxicity.  We  will  recur  again  presently  to  this 
property  as  a  normal  characteristic  of  the  blood  of 
various  animal  species,  and  will  study  it  in  greater 


*  Lkpixk:  Compt.  raid,  de  I' Acad,  des  Sciences,  May  13,  1SS9; 
Soc.  de  Biol.,  1S91,  p.  724. 

t  Roger:    Compt.  rend.  Soc.  Biol.,  1891,  p.  727. 

X  Pozzi-Escot:  Compt.  rend.  deVAcad.de  Mcdeciue  (3),  xi.yii. 
p.  400.  See  also  Pozzi-Escot:  I'Jot  actiiel  de  nos  Connais- 
sances  sitr  les  Oxydases  et  les  Reductases.     Dunod,  publ.,  Paris, 

1  i)OJ. 


62  TOXINS   AND   ANTITOXINS. 

detail  in  a  future  volume  of  this  collection,  devoted 
to  the  immunizing  active  principles. 

Glandular  Secretions. — On  studying  the  venoms 
we  will  see  that  a  certain  number  of  these  products 
are  the  result  of  glandular  secretion.  This  is  a 
general  property  of  the  glands;  and  it  was  Brown- 
Sequard  who  first  drew  attention  to  the  role  played 
by  these  glands,  and  to  the  importance  of  the 
products  that  they  throw  into  the  blood.* 

P.  Noel  showed  later  that  the  testicular  juice 
possesses  a  high  degree  of  activity,  which  he 
attributed  to  an  oxidizing  ferment,  and  which  we 
have  already  mentioned,  spermine. 

The  greater  number  of  the  other  glands  contain 
proteid  matters  and  various  peptones,  more  or  less 
toxic,  with  amides  and  alkaloids. 

Particular  mention  must  be  made  of  the  thyroid 
gland,  the  secretions  of  which  exercise  a  powerful 
action  on  the  nervous  centers  and  on  nutrition. f 
It  appears  reasonable  to  attribute  to  the  secretions 
of  this  gland  a  very  powerful  antitoxic  action,  and 
the  first  proof  of  this  fact  is  that  the  organisms 
deprived  of  this  gland  become  the  seat  of  serious 
derangements ;  the  urines  of  such  organisms  become 
particularly  toxic,  while,  on  the  other  hand,  the 
hypodermic   injections   of   the   aqueous   extract   of 

*  Compt.  rend,  de  V Acad,  des  Sciences,  cxiv,  pp.  1237,  1318, 
1399,  and  1534;   cxv,  p.  375;   and  cxvi,  p.  856. 

I  LAULANI&:   Compt.  rend,  Soc,  de  Biol.,  1894,  p.  187. 


ANIMAL   TOXINS.  63 

the  gland,  when  the  derangements  spoken  of  exist, 
cause  the  immediate  disappearance  of  the  derange- 
ments caused  by  the  excision  of  the  gland.* 

Attempts  have  been  made  to  isolate  the  active 
principle  of  the  glands.  Notkine  isolated  a  tyro- 
proteid,^  which  is  not  sensibly  toxic  to  animals 
who  still  retain  the  gland,  but  which  becomes  toxic 
when  the  gland  is  excised.  It  seems  probable, 
however,  that  this  product  is  not  the  principal 
agent  of  the  thyroid  gland. 

From  the  researches  of  Schaeffer,  Roos,  and  Sig- 
mund  Fraenkel  $  it  results  that  the  active  prin- 
ciple of  the  gland  is  not  a  toxin,  but  a  purely 
chemical  substance,  a  true  leucomaine,  which  has 
received  the  name  thyroantitoxin. 

On  the  other  hand,  Baumann  quite  recently 
extracted  from  the  thyroid  gland  an  iodized  sub- 
stance, which  he  named  thyroiodine .§ 

The  suprarenal  capsules  also  possess  properties 
that  have  often  attracted  the  attention  of  physiol- 
ogists during  the  last  few  years.  They  are  con- 
sidered as  being,  just  like  the  thyroid  gland,  pro- 
ducers  of   antotoxins;    they   destroy,   or   seem   to 


*  Gley:   Cotnpt.  raid.  Soc.  de  Biol.,  1S91,  p.  250. 

t  Se  inline  Medicate,  Apr.  3,  1895,  p.  138. 

%  Wiener  Med.  Blatter,  No.  4S;  and  Gesellsch.  d.  Acrzte  in 
Wien,  Nov.  22,  1895. 

\Zeitschr.  f.  Physiol.  Chan.,  xxi,  pp.  319  and  481;  and  xxn, 
p.  1.  Armand  Gautier:  Chimie  Biologique,  2d  edit-,  pp.  330- 
332.      Masson,   publ. 


64  TOXINS  AND   ANTITOXINS. 

destroy,  toxins  that  are  artificially  introduced  into 
the  circulation. 

Albanese  *  maintains  that  the  function  of  the 
suprarenal  capsules  is  to  neutralize  neurine,  the 
toxic  product  of  the  disassimilation  of  the  nervous 
system ;  this  view,  however,  is  opposed  by  Boinetf 
and  Langlois.  $  On  the  contrary,  it  has  been  defi- 
nitely proven  that  the  suprarenal  glands  exert  a 
specific  action  on  the  poisons  of  muscular  origin. 
Abelous  and  Langlois  §  have  in  fact  demon- 
strated that  the  alcoholic  extract  of  the  muscle 
of  a  decapsulated  animal  has  the  same  properties 
as  the  extract  of  tetanized  muscle ;  the  decapsulated 
animal  gives  ergographic  tracings  analogous  to  those 
afforded  by  tetanized  animals.  The  removal  of  the 
suprarenal  capsule  from  an  animal  brings  results, 
hence,  analogous  to  those  of  fatigue — that  is  to  say, 
that  the  toxic  substances  which  accumulate  as  a 
result  of  the  decapsulation  resemble  those  that 
result  from  muscular  exertion.  The  suprarenal 
capsules  exert  their  action  furthermore  on  other 
toxic  products  as  well,  as  Guieysse||  has  shown, 
and   particularly  on    the    exogenous    poisons.     In 

*  Albanese:  Recherches  sur  les  fonctions  des  capsules 
surrenales.     Arch.  Italiennes  Biol.,  1892. 

t  Botnet:    Compt.  rend.  Soc.  de  Biol.,  Mch.  1896. 

%  See  Compt.  rend,  de  Biol,  et  Arch.  Physiologie,  1 891-1897. 

§  Langlois:    These  de  doctorat  en  Med.,  Paris,  1897. 

||  Guieysse:  Les  capsules  surrenales  du  cobaye,  These,  Paris, 
1901, 


ANIMAL   TOXINS.  65 

conclusion,  it  may  be  said  that  the  matter  concerns 
a  most  important  rdle,  and  we  cannot  do  better  in 
this  respect  than  to  refer  the  reader  to  the  memoir 
presented  by  Sergent  and  Bernard  to  the  Acad6mie 
de  Medecine  in  1902  and  entitled  I'lnsuffisance 
Sitrrciiale* 

*  Encyclopedic  L6aut6,  cccxiv,  Masson,  publ.,  Paris,  1904. 


CHAPTER  IV. 
THE  MICROBIAL  TOXINS. 

There  is  but  one  way  of  characterizing  the  toxic 
poisons  secreted  by  microbes,  and  that  is  to  apply 
to  them  the  name  of  the  microbes  generating  them ; 
thus  the  soluble  and  toxic  poison  of  the  tetanus 
bacilli  has  received  the  name  tetanus  toxin. 

In  toxic  microbial  cultures  it  is  necessary  to 
distinguish  the  toxins  proper  from  the  toxic 
alkaloids  (ptomaines)  which  generally  accompany 
them;  this  is  easily  accomplished  by  evaporating 
the  solution  in  a  vacuum  at  about  300  C,  and 
then  treating  with  alcohol  and  ether,  in  which  the 
alkaloids  are  soluble,  while  the  true  toxins  are 
insoluble.  By  fractional  precipitation  with  alcohol 
it  is  easy  to  isolate  the  peptones  and  true  toxins. 

The  microbial  toxins  possess  two  essential  prop- 
erties; one  the  pyogenic  property,  thanks  to 
which  the  toxins  first  attract,  then  destroy  the 
white  blood  corpuscles  or  leucocytes,  and  trans- 
form them  into  pus,  and  the  other  the  pyretogenic 
property,    which    appears    to    belong    only    quite 

66 


THE   MICROBIAL  TOXINS.  67 

indirectly  to  the  pyogenic  substance.  The  toxins 
in  general  retard  the  heart  action. 

We  will  not  speak  of  the  distinctions  it  has  been 
sought  l«)  establish  between  the  substances  which 
possess  these  different  properties,  but  will  at  once 
take  up  the  discussion  of  several  of  the  microbial 
toxins. 

Anthrax  Toxin*  (from  Bacillus  Anthracis). — We 
will  describe  the  preparation  of  this  toxin  as  a 
type. 

The  cultures  of  the  bacillus  are  made  in  Liebig's 
bouillon,  to  which  has  been  added  0.1%  of  fibrin, 
the  whole  being  carefully  sterilized  for  a  long  time 
at  1  io°  C.  The  cultures  medium  is  inoculated  with 
a  drop  of  blood  taken  from  the  heart  or  spleen  of  an 
animal  that  has  died  of  anthrax.  At  the  end  of  a 
week,  the  culture  is  filtered,  and  the  filtrate  acid- 
ulated with  a  little  acetic  acid  and  precipitated  by 
adding  powdered  ammonium  sulphate.  The  floccu- 
lent  precipitate  is  collected,  washed,  dissolved  in 
distilled  water,  and  dialyzed.  The  dialyzed  solu- 
tion is  concentrated  in  vacuo  at  40-450  C,  and 
precipitated  by  adding  to  it  alcohol.  The  precipi- 
tate formed  is  then  collected  and  dried. f 

*  Arloing,  Cornevin,  'Jhomas:  Lc  Charbon  SymptomaHque, 
1st  edit.,  Paris;  and  Le  Dantec:  La  Bactcridie  du  Charbon, 
Masson,  publ.;  Straus:  Le  Charbon  des  Animaux  ei  de  l' Homme 
Paris,  1887. 

t  Hankin:  British  Medical  Journal,  Oct.  12,  1SS9,  and  July 
12,   1890. 


68  TOXINS  AND   ANTITOXINS. 

In  this  manner  there  is  obtained  a  grayish- 
white  substance  which  is  soluble  in  water,  and 
which  is  fatal  in  large  doses,  but  which,  given  in 
repeated  small  doses,  confers  immunity  against 
anthrax. 

According  to  Hankin,  it  seems  that  the  toxic 
property  of  this  toxin  is  due  to  an  albumose. 

Marchoux  *  has  been  able  to  confer  immunity 
upon  sheep  by  injecting  first  small  quantities  of 
the  filtered  culture  of  the  anthrax  bacilli,  and  then 
the  virulent  anthrax  itself. 

The  animals  thus  rendered  immune  yield  a  serum 
which  may  be  used  as  a  vaccin  against  anthrax, 
and  which  even  possesses  curative  properties  under 
certain  conditions. 

In  every  case  the  acquired  immunity  is  only 
temporary.  We  will  recall  to  recollection  the 
method  employed  by  Pasteur  for  vaccinating 
against  anthrax,  using  attenuated  cultures,  a 
method  which  is  practiced  daily  at  the  present  time.t 

From  the  cultures  of  symptomatic  anthrax 
(Bacillus  Chauvas)  Chauvee  extracted  a  very  active 
toxin  which  can  withstand  without  impairment 
a  temperature  of  no°'C.f     Roux  §  has  shown  that 


*  Annal.  Instit.  Pasteur,  ix,  p.  785. 

f  Chamberland:  Le  Charbon  et  la  Vaccination  Charbonneuse, 
Paris,  1887.     Petermann:    Annal.  Instit.  Pasteur,  vi,  p.  32. 
%  Deutschmann:   Annal.  Instit.  Pasteur.,  vm,  p.  403. 
§  Annal.  Inst.  Pasteur,  Feb.  1888. 


THE  MICROBIAL  TOXINS.  69 

the  scrum  of  animals  that  have  succumbed  to  the 
symptomatic  anthrax  is  capable  of  vaccinating 
against  this  disease;  we  have  here  a  new  proof 
that  the  antitoxin  is  in  fact  a  product  of  the  defense 
of  the  cells  of  the  organism,  and  the  author  men- 
tioned has  been  able  to  vaccinate  guinea-pigs  by 
injecting  into  the  peritoneum  culture  bouillon 
sterilized  by  heating  to  1150  C.  or  by  filtering 
through  porcelain. 

Tubercular  Toxin.  —  The  culture  bouillons  of 
Koch's  bacillus  contain  one  or  more  active  sub- 
stances which  constitute,  and  which  is  at  the 
present  designated  as,  tuberculin.*  Koch's  thera- 
peutic tuberculin  is  obtained  by  evaporating  to 
one-tenth  its  volume  a  culture  bouillon  of  Koch's 
tubercle  bacilli  prepared  from  a  4-per  cent,  gly- 
cerinic  mutton  bouillon,  and  filtering  through  porce- 
lain. By  fractional  precipitation  it  is  possible  to 
obtain  from  the  crude  tuberculin  so  prepared  a 
product  which  is  considered  as  pure  tuberculin,  and 
which  possesses  considerable  activity. 

Prolonged  boiling  on  the  water-bath  completely 
destroys  the  activity  of  this  tuberculin,  which 
moreover  hardly  ever  keeps  longer  than  three 
weeks.  It  has  been  found  possible  to  preserve  it 
for   an   indefinite   period,    however,    by   adding   to 


*  Auclair:     Thlse  de  doctorat,    Paris,    1S97;     and   Arch,   dc 
Midecine,  exp.  1898. 


?0  TOXINS   AND   ANTITOXINS. 

it  30  to  40  per  cent,  of  glycerin.     It  possesses  all 
the  general  reactions  of  albuminoids. 

Tuberculin  is  not  toxic  in  the  proper  sense  of 
the  word.  Injected  in  small  quantities  into  the 
healthy  human  being  *  and  into  healthy  animals,  it 
exerts  no  effect;  on  the  other  hand,  however,  in 
tubercular  organisms,  even  in  incipient  stages  of 
the  disease,  even  where  it  is  almost  impossible  to 
make  a  clinical  diagnosis,  the  injection  of  very  small 
quantities  develops  a  lively  and  characteristic 
reaction,  f 

Grasset  and  Vedel  consider  the  tuberculin  as  an 
excellent  means  of  diagnosing  tuberculosis  in  man, 
but  in  such  a  case  it  is  necessary  to  operate  with 
the  greatest  caution,  with  very  small  quantities 
of  the  tuberculin,  and  to  feel,  in  some  sort,  the 
sensitiveness  of  the  patient,  particularly  in  the 
case  of  children. 

It  is  chiefly  for  the  diagnosis  of  tuberculosis  in 
cattle,  however,  that  tuberculin  is  valuable. 
Thanks  to  Nocard,  the  procedure  has  to-day  become 
a  common  practice.  The  injection  of  a  fairly 
large  dose,  0.3  to  0.4  Gm.,  according  to  the  size 
of  the  animal,  causes,  in  about  ten  hours  or  so, 
if  the  animal  is  tuberculous,  a  strong  febrile  reac- 


*Koch:  Deutsch.  Med.  Woch.,  Nov.  13,  1890-1897,  No.  14, 
p.   209. 

f  Annal.  de  Vlnstit.  Pasteur,  v,  p.  191;  Arch,  de  la  Soc.  Biol, 
de  Saint-Pttersbourg,  1,  p.  213. 


THE  micr<  >BIAL  TOXINS.  71 

tion  with  an  elevation  of  temperature  of  i.g  to 
3°  C,  whereas  if  the  animal  is  not  tuberculous 
no  such  reaction  takes  place. 

Cases  in  which  tuberculosis  is  far  advanced,  and 
in  which  the  organism  is  impregnated  with  tuber- 
culin, do  not  react  after  the  injection  of  tuberculin.* 

Tuberculin  does  not  confer  immunity,  and  the 
bacillus  retains  all  its  virulence,  even  in  injected 
tissues;  nevertheless,  the  return  to  health  of  ani- 
mals in  which  injections  have  been  recently  made 
may  be  due  to  the  action  of  large  doses  of  the 
serum;  and  on  the  other  hand  the  tuberculin,  in 
large  quantities,  may  render  the  location  unsuit- 
able for  the  development  of  the  tubercle  bacilli. 

Diphtheria  Toxin. — The  most  characteristic  prop- 
erty of  the  diphtheria  bacillus  is  the  production,  in 
culture  media,  of  a  special  toxic  substance  which 
has  been  named  diphtheritic  toxin;  this  name, 
however,  has  come  to  be  also  extended  to  a  liquid 
in  which  the  bacilli  have  lived,  and  which  has 
been  sterilized  by  filtration  or  by  any  other  suita- 
ble process. 

Roux  and  Yersin  f  were  the  first  to  affirm  that 
diphtheria  is  an  autointoxication  caused  by  a  very 
active  poison  formed  by  the  microbe  in  the  restricted 
locality  where  it  develops.     In  order  to  obtain  this 

*  Nocard  and  Leclainchb:  Les  Maladies  Microbiennes 
des  Animaux. 

t  Annal.  dc  VInstit.  Pasteur,  n,  p.  632,  and  vm,  p.  611. 


72  TOXINS  AND   ANTITOXINS. 

toxin  *  a  culture  of  the  bacillus  is  first  made  in  a 
mutton  bouillon  made  strongly  alkaline  with  so- 
dium carbonate  (10  grams  per  liter),  and  with  the 
addition  of  2  per  cent,  of  peptone.  At  the  end 
of  about  one  month,  the  culture  being  kept  at 
about  370  C,  the  liquid  is  filtered  through  porce- 
lain. It  is  indispensable  to  employ  a  very  viru- 
lent bacillus;  it  is  hence  frequently  advantageous 
to  increase  the  virulence  and  toxigenic  power  of 
the  bacilli  it  is   desired   to  use. 

The  toxic  liquid  obtained  is  exceedingly  power- 
ful: 0.1  Cc.  kills  a  rabbit  in  forty-eight  hours. 
This  toxin  is  very  sensitive  to  the  effects  of  heat. 
When  heated  to  650  C.  it  loses  almost  all  its  toxicity; 
at  700  C.  it  becomes  innocuous ;  and  it  only  re- 
quires to  be  heated  to  ioo°  C.  for  fifteen  minutes 
in  order  to  lose  all  immediate  activity  even  in  large 
doses.  Nevertheless  toxins  thus  weakened  are 
capable  of  proving  fatal  to  an  animal  even  after 
five  or  six  months. 

Light,  oxygen,  ozone  and  all  oxidizers  destroy  the 
active  principle  of  the  diphtheria  toxin,  which  is, 
moreover,  rendered  almost  inactive  by  organic  acids. 

This  toxin  is  capable  of  diffusing  through  animal 
membranes,  a  fact  that  is  in  agreement  with  the 
toxic  effect  seen  in  a  subject  attacked  with  diph- 


*  See  Spronk:    Annal.  de  I'Instit.  Pasteur,  ix,  p.  785;    Ibid., 
x,  p.  333;  Martin,  Ibid.,  xn,  p.  26;  Spronk,  Ibid.,  xn,  p.  711. 


THE   MICROBIAL  TOXINS.  73 

theria,  and  due  to  the  toxin  passing  through  the 
mucosa.  In  spite  of  this  property,  however,  the 
diphtheritic  poison  may  be  taken  into  the  stomach 
without  any  pernicious  results. 

Roux  and  Yersin  have  shown  that,  like  all  the 
diastases,  it  may  be  precipitated  from  its  solutions 
by  the  development,  within  these,  of  certain  pre- 
cipitates, particularly  calcium  phosphate.  It  is 
precipitated  from  its  solutions  by  alcohol,  as  has 
been  observed  also  in  the  case  of  diastatic  solutions. 
All  the  toxic  substance  is  contained  in  the  albu- 
minous precipitate  thus  obtained ;  but  the  prolonged 
action  of  alcohol,  or  repeated  successive  precipita- 
tions, alter  it  finally.  Diphtheria  toxin  is  likewise 
precipitated  by  the  reagents  for  albumoses,  par- 
ticularly sodium  sulphate  in  saturated  solution. 
This  procedure  has  been  utilized  by  Brieger  and 
Fraenkel  for  preparing  the  pure  toxin,  which 
they  obtained  in  the  form  of  very  light,  brilliant 
white,  amorphous  flocks,  affording  all  the  principal 
reactions  of  the  soluble  albumoses  (biuret,  xantho- 
proteic, Millon's),  and  which  they  characterized 
as  a  toxalbumin. 

On  injecting  into  healthy  animals  this  diphtheria 
toxin  attenuated  by  sufficiently  heating  at  700  C, 
employing  at  first  small  doses,  and  gradually 
increasing,  it  is  possible  to  immunize  them  against 
diphtheria,  as  was  first  demonstrated  by  Carl 
Fraenkel. 


74  TOXINS  AND   ANTITOXINS. 

Roux  and  Martin,  who  have  specially  studied 
this  procedure,*  have  shown  that  a  horse  may  be 
easily  immunized  by  injecting  into  the  animal  the 
toxin  diluted  with  a  third  of  its  volume  of  Gram's 
iodine  solution,  and  in  successively  increasing 
doses.  The  initial  dose  is  0.25  Cc. ;  then,  after 
two  days,  0.5  Cc.  of  the  same  toxin  is  injected, 
and  in  like  manner  the  dose  is  increased  up  to  the 
eighteenth  day,  when  the  pure  toxin  is  injected, 
at  first  in  small  doses,  which  are  gradually  in- 
creased so  that  at  the  end  of  two  or  three  months 
injections  of  80  Cc.  of  the  pure  toxin  may  be  given 
without  danger;  the  animal  is  then  completely 
immunized. 

The  serum  of  an  animal  rendered  immune  in  this 
manner  contains  a  diphtheria  antitoxin  which 
possesses  high  power.  A  guinea-pig  which  has 
received  an  injection  of  0.0 1  Cc.  of  the  antitoxin  is 
perfectly  capable  of  withstanding  a  lethal  dose  of 
0.5  Cc.  of  the  toxin.  The  antidiphtheria  serum 
thus  obtained,  and  in  almost  limitless  quantities, 
from  an  immunized  animal,  is  capable  of  saturating 
the  therapeutic  diphtheritic  toxin,  and  has  to-day 
taken  rank  in  therapeutics  as  the  most  efficacious 
remedy  in  diphtheria.  Injected  in  varying  doses, 
it  confers  a  temporary  but  immediate  immunity. 


*  Contribution  a  1' Etude  de  la  Dipht6rie.     Annal.  de  VInstit. 
Pasteur,  vm,  p.  609;  Ibid.,  p.  640. 


THE    MICR(  >B1  \L  TOXINS.  75 

Nevertheless  antidiphtheria  scrum  must  noi  be 
considered  as  an  antidote;  and  in  pathological 
diphtheria,  the  more  serum  is  required  the  later 
it  is  used.*     In  certain  cases,  it"  employed  too  late, 

it   may  prove  ineffective. 

Tlu-  preventive  action  of  the  serum  is  remarkable. 
In  i  o  ooo  inoculated  east's  Helming  and  Ehrlich 
have  had  but  10  cases  of  diphtheria,  and  these 
were,  moreover,  of  a  benign  character.  The  dura- 
tion of  the  immunizing  action  appears  to  be  from 
three  weeks  to  two  months. 

This  diphtheria  antitoxin  was  first  prepared 
by  tiuerin  and  Mace  f  by  adding  to  the  anti- 
diphtheria  serum  a  large  volume  of  alcohol,  wash- 
ing the  precipitate,  and  drying  it  in  a  vacuum. 
It  is  soluble  in  water,  and  loses  its  activity  when 
heated  to  650  C.  Wassermann  |  has  proposed 
to  extract  it  from  the  milk  of  immunized  animals, 
by  first  coagulating  the  milk  by  rennet  in  the 
presence  of  sodium  chloride,  filtering,  and  removing 
the  fat  from  the  clear  liquid  by  means  of  chloroform. 
After  decanting,  the  clear  solution  obtained  is 
precipitated  by  adding  to  it  30  to  33  per  cent,  of 
ammonium  sulphate.  The  precipitate  is  dried  in 
a  vacuum  on  a  polished  porcelain  slab  after  having 


♦  Baybux:   These  de  Doctorat,  Paris,  1899. 
t  ( 'ompt.  rend,  de  V  Acad,  des  Sc,  Apr.  5,  1S95. 
I  Zeitschr.  jilr  Hygiene,  xvm,  p.  235. 


76  TOXINS   AND    ANTITOXINS. 

first  been  strongly  expressed.  It  is  then  dissolved 
in  water.* 

Tetanus  Toxin.  —  The  fact  that  the  tetanus 
bacillus  never  penetrates  to  the  interior  of  the 
organism  enabled  us  long  ago  to  foretell  that  it 
secretes  a  very  powerful  toxin  capable  of  dia- 
lyzing  and  diffusing  through  the  economy.  Kuno 
Faber  was  the  first  to  fully  recognize  the  fact  that 
the  culture  bouillon  of  this  bacillus,  fully  steril- 
ized by  filtration  through  porcelain,  possesses  an 
exceedingly  high  toxicity,  and  exerts  a  toxic 
effect  on  50  000  000  times  its  own  weight  of  living 
organism.  Brieger  had  previously,  however,  ex- 
tracted three  ptomaines  from  the  cultures  of  the 
bacillus  —  tetanin,  tetanotoxin,  and  spasmotoxin.^ 
In  order  to  obtain  a  highly  active  liquid,  the  same 
culture  medium  is  inoculated  several  times  in 
succession,  but  filtering  each  time  before  the  new 
inoculation;  the  ^microbes  greatly  increase  in 
number  after  each  fresh  inoculation,  and  the  toxic 
substance  developed  by  them  accumulates.! 

Experiment  has  shown  that  the  culture  bouillon 
thus   obtained   contains    two   kinds   of   toxic   sub- 


*  Roux  and  Martin:  Contribution  a  l'Etude  de  la  Diphteria. 
Annal.  de  Vlnstit.  Pasteur,  viii,  p.  512. 

f  Die  Pathogenese  des  Tetanus.  Berlin.  Klin.  Wochenschr. 
1890,  No.  31. 

JNaillard:  Compt.  rend,  de  V Acad,  des  Sciences,  exx,  p# 
1181. 


THE   MICROBIAL  TOXINS.  77 

stances* — highly  toxic  alkaloidal  bases  (ptomaines, 
tetanin,  tetanotoxin,  etc.),  and  a  true  toxin,  pos- 
sessing diastatic  properties,  and  of  almost  incredi- 
ble toxic  power. 

This  toxin  had  already  been  isolated  by  Kitasato. 
It  is  a  toxalbumin,  and  is  very  sensitive  to  the 
action  of  heat.  A  temperature  of  650  C,  main- 
tained for  30  minutes,  renders  it  quite  inactive; 
and  it  becomes  oxidized  and  is  destroyed  by  the 
action  of  the  air  in  the  presence  of  light. 

Briegcr  and  Boer.f  by  precipitating  with  zinc 
chloride  the  filtered  culture  bouillon,  obtained 
a  pure,  amorphous  tetanus  toxin,  which  they  also 
considered  as  a  toxalbumin,  and  which  possesses 
exceedingly  toxic  properties. 

If  a  precipitate  be  caused  to  form  in  these  toxic 
solutions,  as,  for  instance,  a  precipitate  of  cal- 
cium phosphate,  this  carries  down  with  it  all  the 
toxin  present  in  the  liquid.  0.0005  Gm.  °f  this 
precipitate  is  surely  fatal  to  a  guinea-pig. 

Dozon  and  Cournemont  have  observed  that 
even  in  doses  of  300  to  400  Gm.  of  the  filtered  cul- 
ture liquid,  this  toxin  is  not  immediately  toxic 
to  a  horse,  but  kills  the  animal  only  after  a  period 
of  incubation  of  at  least  twenty-four  hours.  The 
blood  of  such  an  animal,  however,  is  immediately 


*  Annal,  Instil.  Pasteur,  v,  15. 

t  Deutsche  Med,  Wochenschr.,  No.  49,  Dec.  3,  1S96, 


78  TOXINS  AND  ANTITOXINS. 

and  directly  fatal  to  animals  into  which  it  is 
injected.* 

Experiment  has  shown  that  animals  that  have 
been  cured  of  tetanus  possess  no  immunity  what- 
ever against  tetanus;  nevertheless  Behring  and 
Kitasato  f  first,  and  Wassermann  and  Kitasato  later 
on,  succeeded  in  preparing  a  tetanus  antitoxin.  To 
obtain  this,  the  immunization  of  the  animal,  horse 
or  cow,  is  effected  by  injecting  increasing  quan- 
tities of  the  toxin,  more  Or  less  attenuated  by  mixing 
it  with  Gramm's  iodine  solution ;  the  immunization 
is  easily  and  rapidly  accomplished  by  the  process 
devised  by  Roux  and  Vaillard.f 

The  immunized  animals  yield  a  serum  which, 
mixed  with  tetanus  cultures,  renders  these  innocu- 
ous, and  which  enjoys  an  antitoxic  power  that 
borders  on  the  marvelous.  §  A  quintillionth  of  a 
cubic  centimeter  of  the  serum  per  gramme  weight 
of  a  live  mouse  suffices  to  protect  the  animal  from 
an  otherwise  fatal  quantity  of  tetanus  toxin. || 

This  serum  is  nevertheless  powerless  to  preserve 
man  in  cases  of  acute  tetanus ;  it  confers  an  imme- 
diate, but  only  transitory,  immunity. 

As  to  its  mode  of  action,  it  appears  to  cause 
a  permanent  condition  of  excitation  or  of  nutri- 

*  Compt.  rend.  Soc.  Biol.,  1893,  p.  294;  Ibid.,  1S94,  p.  878. 

f  Deutsch.  Med.  Wochenschr.,  1890. 

X  Annal.  Instit.  Pasteur,  vn,  p.  64. 

§  Nocard:   Bull,  de  I' Acad,  de  Medecine,  Oct.  22,  1895. 

|)  Naillard:  Compt.  rend,  de  I' Acad,  de  Sciences,  cxx,  p.  1181. 


THE   MICROBIAL   TOXINS.  79 

tive  reaction  of  the  cells,  which  makes  these  resist- 
ant to  the  poison.  As  in  the  case  of  the  other 
toxins,  the  quantity  of  antitoxin  necessary  to 
protect  an  organism  is  so  much  greater  the  later 
the  treatment  is  applied. 

Mallein  (Toxin  of  Glanders). — Among  the  soluble 
products  secreted  in  the  culture  media  by  the 
glanders  bacilli,  there  are  found  true  toxins  to 
which  are  ascribed  certain  symptoms  of  glanders 
infection.  These  toxins  have  been  isolated  and 
designated  by  the  name  mullein.  First  prepared 
by  Helman  and  Kalmino,  mallein  was  later  on 
specially  studied  by  Roux  and  Nocard,  and,  in 
consequence  of  the  researches  of  the  last-men- 
tioned scientist,  it  has  acquired  great  importance.* 
It  is  obtained  by  sterilizing  at  no°  C.  cultures  of 
the  glanders  bacillus  made  with  mutton  bouillon 
with  the  addition  of  salt,  glycerin,  and  peptones. 
To  isolate  the  toxin  the  culture  bouillon  is  first 
sterilized  by  heating  for  half  an  hour  in  an  auto- 
clave at  ioo°  C.  It  is  then  filtered,  concentrated 
to  one-tenth  its  volume  on  a  water-bath,  and  fil- 
tered through  a  Chardin  filter.  The  mallein  is 
thus  obtained  in  the  form  of  a  brown  syrupy 
liquid  containing  half  its  weight  of  glycerin. 

This  solution  keeps  well  when  kept  from  air, 
light,  and  heat.     In  practice  it  is  employed  in  10-per 

♦  Nocard:   Lcs  Maladies  microbiemtfs  <jtes  anitnaux,  Paris. 


80  TOXINS   AND  ANTITOXINS. 

cent,  solution  in  phenolated  water  (5:1000).  The 
mallein  may  be  precipitated  from  the  crude  solu- 
tion by  the  addition  of  alcohol,  as  recommended 
by  Foth.  Foth's  mallein  occurs  as  a  white,  light 
powder,  very  easily  soluble  in  water. 

Mallein  enjoys  a  very  important  role  in  veteri- 
nary therapeutics,  a  role  analogous  to  that  of 
tuberculin,  permitting  the  diagnosis  of  incipient 
glanders.* 

Experience  has  shown  that  in  animals  already 
attacked  by  glanders,  even  if  ever  so  slightly,  the 
thermic  reaction  never  fails  when  0.25  Cc.  of  the 
mallein  solution  is  injected.  In  healthy  animals, 
however,  the  injection  of  mallein,  even  in  much 
larger  quantities,  causes  no  apparent  effect.  In 
animals  attacked  by  glanders  the  reaction  attains 
its  maximum  in  twelve  hours,  and  several  days 
are  required  for  the  temperature  to  return  to 
normal,  f 

According  to  Nocard,  mallein  possesses  no  immu- 
nizing properties  whatever.  X 

Typhoid  Toxin. — This  is  obtained,  like  the  other 
microbial  toxins,  from  a  culture,  prepared  with 
more    or    less    difficulty,    from    Eberth's    typhoid 

*  Strauss:    Arch,  de  Medic,  experiment.,  1886. 

t  Cadiot  and  Roger:  Compt.  rend.  Soc.  Biol.,  1895,  p.  770; 
Wladimirow:  Arch,  des  Sciences  Biol,  de  St.-Petersbourg,  iv, 
p.  30;  Bourges  and  Mery:  Soc.  de  Biol.,  Feb.  5,  1878. 

%  Galtier:  Compt.  rend,  de  V Acad,  des  Sciences,  xcn,  p. 
303;  Strauss:  Arch,  de  Medic,  experiment  1,  p.  489. 


THE  MICROBIAL  toxins.  8i 

bacillus.  This  toxin,  injected  into  guinea-pigs, 
dcvcli  >ps  iii  them  typhoid  fever. 

In  the  solution  there  occurs  a  ptomaine,  which 
has  been  isolated  by  Brieger,  and  which  gives  rise 

to  almost  all  the  phenomena  of  typhoid  fever;  this 
ptomaine  is  called  typhotoxin* 

The  same  author,  in  collaboration  with  Fraenkel,f 
later  on  isolated  a  toxalbumin  from  the  culture 
bouillon  ol  the  typhoid  bacillus.  Sanarclli  \  ob- 
tained an  active  toxin  by  macerating  for  several 
days  at  6o°  C.  a  month-old  culture  of  the  typhoid 
bacillus  made  with  a  2 -per  cent,  glycerin-bouillon. 
Chantemesse  has  also  published  a  process  which 
yields  a  highly  virulent  toxin.  § 

Chantemesse  and  Widal  ||  have  shown  that  on 
injecting  into  an  organism  increasing  quantities 
of  the  sterilized  cultures  of  Eberth's  Bacillus,  it  is 
possible  to  fully  immunize  an  animal  against  the 
bacillus  itself,  and  even  also  against  the  Bacillus 
coli  communis.  The  operation,  however,  is  tedious 
and  painful.  The  serum  of  immunized  animals 
possesses  preventive  and  curative  properties  respect- 
ing the  effects  of  typhoid  bacilli. 


*  Brieger:  Microbes,  Ptomaines  et  Maladies,  Doin,  publ., 
Paris,  1SS7;   Luff:    Brit.  Med.  Journ.,  1SS9. 

f  Berlin.  Klin.  Wochenschr.,  1890. 

J  Annal.  de  I'Instit.  Pasteur,  vm,  p.  10.3. 

%Compt.  reiui.  Sac.  de  Biol.,  p.  232,  Jan.  30,  1807.  Congres 
d' Hygiene  de  Madrid,  1898. 

||  Annal.  Instit.  Pasteur ,  VI,  p.  755;  Sanarelli:  Ibid., -p.  721, 


82  TOXINS   AND   ANTITOXINS. 

A  dose  of  the  filtered  culture,  which  is  fatal  to 
a  guinea-pig,  becomes  innocuous  when  mixed  with 
0.5  Cc.  of  the  serum  of  a  vaccinated  guinea-pig; 
6  Cc.  of  the  serum  injected  six  hours  after  an 
injection  of  the  virulent  culture,  hence  when  this 
is  in  full  action,  suffice  to  save  the  animal.*  So 
far  as  the  human  being  is  concerned,  the  results 
obtained  have  not  been  sufficiently  satisfactory. 

The  culture  bouillon  of  the  Bacillus  coli  com- 
munis, which  is  closely  allied  to  Eberth's  bacillus, 
also  contains  soluble  toxic  substances  which  have 
been  named  coli-bacillus  toxin.  This  substance, 
which  is  produced  only  in  small  quantity  by  the 
microbe,  is  fatal  only  in  very  large  doses. 

Cholera  Toxin. — Very  little  is  known  regarding 
the  toxic  products  of  the  spirillium  cholerse; 
nevertheless,  the  fact  that  typical  cholera  exhibits 
every  symptom  of  the  action  of  a  toxic  agent 
demonstrates  quite  clearly  the  elaboration  of  some 
toxic  substance  within  the  cultures  of  this  microbe. 

Villiers  f  found  in  it  a  liquid  ptomaine ;  Klebs  % 
found  another  and  crystallizable  ptomaine;  while 
Pitai  discovered  in  it  a  toxin  unalterable  by  heat, 
and  which  he  considered  as  a  toxopeptone.  Accord- 
ing to   Gamaleia  §   there  is  present  a   true  toxin, 

*  Funck:  La  Serotherapie  de  la  Fievre  Typhoide,  1,  Brussels. 
1896. 

f  Compt.  rend,  de  V Acad,  des  Sciences,  Jan.  12,  1885. 
%  Klebs:    Allgem.  Wien.  Med.  Zeit.,  1887. 
§  Arch,  de  Med.  Experim.,  iv,  p.  173. 


THE  MICROBIAL  TOXIN'S.  83 

alterable  by  heat,  and  the  reactions  of  which 
entitle  it  to  be  considered  as  a  nucleo-albumin ;  he 
has  also  found  in  it  a  toxic  nuclein. 

These  toxic  substances  arc  found,  according  to 
Gamaleia,  Pfeiffer,  and  Sanarelli,*  confined  during 
the  life  of  the  microbe  within  its  cellular  envelope, 
and  does  not  diffuse  through  this.  Metchnikoff 
and  Roux  are  of  the  contrary  opinion,!  however 
and  they  have  prepared  a  toxin  almost  insensitive 
to  a  temperature  of  ioo°  C,  and  precipitable  from 
its  solutions  by  ammonium  sulphate  or  strong 
alcohol;  the  toxin  is  a  toxalbumin.  This  toxin  is 
quite  toxic ;  one-third  of  a  cubic  centimeter  suffices 
to  kill  100  Gm.  of  guinea-pig  in  18  hours ;  with  larger 
doses,  death  is  almost  immediate. 

By  immunizing  guinea-pigs,  rabbits,  and  horses 
with  this  cholera  toxin,  Metchnikoff  and  Roux 
obtained  a  serum  which  is  distinctly  antitoxic  for 
rabbits.  Nothing  absolutely  certain  has  been  found 
as  to  its  action  on  man.  J 


We  will  not  dwell  longer  here  on  the  toxins  of 
microbial  origin.  It  appears  evident,  however, 
from  what  has  been  stated   above,  that  the  great 

*  Annal.  de  I'Instit.  Pasteur,  ix,  p.  129. 

t  Ibid.,  x,  p.  257. 

X  Haffkine:  Compt.  rend,  de  I' Acad,  des  Sciences,  1S02; 
Metchnikoff:  Annal.  de  I'Instit.  Pasteur,  vu,  p.  403;  and 
Roux:  Ibid.,  x,  p.  253. 


84  TOXINS  AND   ANTITOXINS. 

majority,  if  not  all,  of  the  virulent  microbes  manifest 
their  virulence  by  means  of  toxic  secretions.  Almost 
every  one  of  these  toxins  has  been  the  subject  of 
study.  They  would  otherwise  not  have  interested 
us  here,  where  our  main  object  was  but  to  dwell 
upon  the  general  properties. 


CHAPTER    V. 

THE  VENOMS. 

General  Nature  of  Venoms. — The  venoms  are 
more  or  less  toxic  products  secreted  by  certain 
reptiles,  batrachians,  and  fish;  by  a  large  number 
of  invertebrates;  by  arachnids,  apids,  scorpionids, 
araneids,  and  a  large  number  of  other  insects. 

The  venoms  are  toxic  principles  very  closely 
allied  to  the  microbial  toxins;  like  the  latter,  they 
form  two  classes,  the  one  alkaloidal,  the  other 
proteid,  possessing  a  true  diastatic  character. 
They  closely  resemble  the  microbial  toxins,  more- 
over, by  the  fact  that  they  are  capable  of  being 
transformed  into  vaccins  by  attenuation  of  their 
virulence,  by  the  action  of  heat  or  chemical  re- 
agents, and  of  leading  to  habituation  of  use  and 
the  conference  of  immunity.*  Moreover,  like  the 
various  viruses,  the  serum  of  immunized  animals 
is  antivenomous,  so  that  if  injected  into  the  veins 
or  beneath  the  skin  of  non-immunized  animals,  the 

*  Annal.  de  I'In&tit.  Pasteur,  VIII,  p.  2S1;  Journ.  of  Physio/., 
vin,  p.  203;  and  Soc.  dc  Biol.,  1894,  p.  1 11. 

85 


86  TOXINS   AND  ANTITOXINS. 

serum  confers  upon  them  an  immunity  against 
venom  which  lasts  for  some  time. 

These  venoms,  like  the  microbial  toxins,  possess 
but  slight  toxicity  when  absorbed  via  the  stomach. 
Fraser,  utilizing  a  method  previously  advocated, 
succeeded,  by  following  this  method,  in  vaccinating 
against  serpent-venom  by  causing  the  absorption 
by  animals  of  constantly  increasing  doses  of  venom. 

It  was  thus  possible  to  make  the  animals  with- 
stand doses  a  thousand  times  greater  than  the 
ordinary  lethal  dose;  the  blood  and  serums  of 
these  animals  at  this  point  possessed  immunizing 
properties,  and  this  property  passed  by  heredity 
to  the  offspring,  to  which  it  is  transmitted  by 
the  blood  itself,  and  by  the  milk  during  feeding. 

Along  with  these  resemblances  between  the 
venoms  and  toxins,  attention  must  be  called  to  a 
very  important  difference.  As  we  have  already 
seen,  the  action  of  the  toxins  on  the  organism  is 
always  preceded  by  a  certain  period  of  incubation; 
the  action  of  the  venoms,  on  the  contrary,  is  almost 
instantaneous,  and  in  this  respect  they  behave  like 
chemical  agents  and  alkaloidal  toxins. 

If  the  venoms  are  preserved  in  a  moist  condition, 
they  change  because  they  undergo  putrefaction, 
which  is  generally  the  case  with  all  diastatic  sub- 
stances, and  particularly  the  toxins. 

It  is  interesting  to  note  that  animals  which  have 
been  bitten  by  a  venomous  serpent,  but  which, 


THE    VENOMS.  87 

for  some  reason  or  other,  have  not  succumbed   to 

the  venom,  never  recover  their  former  condition; 
if  they  were  young,  their  functions  cease  to  develop, 
and  they  droop;  if  they  are  adults,  their  general 
condition  remains  that  of  stupefaction. 

Venomous  Serpents. — Among  the  venomous  ser- 
pents,* the  most  important  as  well  as  the  most 
dangerous  are  the  following:  Cobra  di  capello 
(Naja  tripudians,  the  hooded  cobra)  and  its  ana- 
logues, the  black  Naja,  Naja  hage,  etc.;  the  elops 
(coral  serpent) ;  the  bungurus  of  Bengal  and 
Burmah;  the  Platycercus  proteroglyphia,  which  is 
found  chiefly  in  the  waters  of  the  Indian  Ocean; 
the  crotalian  solenoglyphs  of  the  two  Americas, 
and  among  which  in  particular  are  the  rattlesnake, 
the  fer-de-lance  (the  yellow  viper)  of  Martinique; 
the  surucucu  of  Guiana;  and  the  moccasins  and 
copperheads  of  Texas  and  Florida.  Lastly,  the 
entire  group  of  viperian  solenoglyphs,  among 
which  are  the  Echidnas,  the  bite  of  some  of  which, 
for  instance  the  daboia  or  echidna,  is  dreadful ;  the 
African  vipers,  among  which  may  be  mentioned 
the  horned  viper,  the  bite  of  which  will  kill  a  camel ; 
the  springing  viper  of  Congo,  and  the  rhinoceros- 
viper  of  Gabun ;  the  European  vipers,  the  most 
dangerous  of  which  is  certainly  the  asp  of  France, 
which  is  exceedingly  numerous  in  certain  regions. 

*Calmette:  LeVe.iin    'es Serpents,  Paris,  1896. 


88  TOXINS  AND  ANTITOXINS. 

The  effects  of  the  bites  of  venomous  serpents  on 
man  and  animals  are  generally  well  known  to  the 
public;  it  is  well  to  recall  them,  nevertheless. 
From  the  moment  the  bite  has  been  inflicted,  com- 
plete symptoms  of  poisoning  develop,  attended  by 
a  condition  of  extreme  and  increasing  weakness, 
with  vomiting,  hemorrhage,  and  decomposition  of 
the  blood.  There  are,  besides,  particular  effects 
which  vary  with  every  venom. 

The  following  table  by  Calmette  *  gives  the 
comparative  toxicity  of  various  venoms,  taking  as 
the  standard  of  comparison  the  quantity  sufficient 
to  kill  a  rabbit  in  three  or  four  hours: 

Naja  tripudians o .  00047 

Naja  hage o .  0003-0 .  0007 

Acanthophis  antarctica 0.001 

Ceraste o .  001 7-0 .  002 1 

Haplocephalus  variegatus 0.0025 

Trigonocephalus o .  0025 

Nature  of  Serpent-venoms.  —  These  venoms  are 
homogeneous  liquids,  somewhat  more  dense  than 
water,  in  which  they  are  soluble,  slightly  colored 
green  or  yellow,  transparent,  and  insoluble  in 
alcohol;  they  contain  from  30  to  35  per  cent,  of 
solid  matter.  When  fresh,  they  have  a  slightly 
acid    reaction.     Towards    chemical    reagents,    and 

*  Calmette:  Annal.  Instil.  Pasteur,  viii,  p.  276;   ix,  p.  229. 


THE   VENOMS.  89 

particularly  acids,  they  behave  like  albuminoids; 
almost  all  the  combinations  they  afford  with  the 
various  albuminoid  reagents  are  active,  despite 
their  insolubility.  According  to  Gautier,  they  are 
decomposed  by  caustic  potash. 

According  to  numerous  researches,  oxidizers  like 
potassium  permanganate,  the  hypochlorites,  hydro- 
gen peroxide,  and  gold  chloride  (in  i%  solution) 
destroy  the  venoms;  in  certain  cases  when  imme- 
diately injected  hypodermically  in  the  poisoned 
region,    these    substances    are    excellent    antidotes 


tn  vivo 


* 


We  shall  not  here  enter  upon  a  detailed  study 
of  the  toxic  albuminoid  principles  of  serpent-venoms ; 
moreover,  our  knowledge  is  rather  vague,  as  it  is,  on 
a  number  of  points.  It  will  suffice  us  to  know  that, 
taken  altogether,  the  active  albuminoids  of  these 
venoms  are  numerous,  and  that  each  venom  has 
its  own  particular  active  constituents,  differing 
according  to  the  species  and  variety  of  the  snake. 

Each  one  of  these  substances  acts  more  or  less 
rapidly,  and  may  be  associated  with  different 
principles  which  give  rise  to  the  variability  of 
the  action  of  these  toxic  agents.  Among  these 
toxic  albuminoids,  the  most  virulent  appear  to  be 
true    albumins    and    globulins,    followed    by    the 

♦  Winter  and  Blyth:  The  Analyst,  1877,  p.  2°4^  Lacirpa: 
Conipt.  rend,  de  VAcad.  des  Sciences,  xcm,  p.  466;  Calmette: 
Annal.  Instit.  Pasteur,  vi,  p.  175,  and  vin,  p.  278. 


90  TOXINS   AND   ANTITOXINS. 

nucleo-albumins,  as  we  have  already  stated;  there 
are  also  found  in  venoms  alkaloidal  bases,  but 
these  principles  are  present  only  in  very  slight 
quantity.  These  bases  are  but  very  slightly  toxic 
compared  with  the  toxins  that  accompany  them. 

Natural  Immunity  towards  Serpent-venoms. — 
Certain  animals  exhibit  a  natural  immunity  toward 
snake-bites;  among  them  are  the  snakes  them- 
selves, the  hog,  the  hedgehog,  and  the  mongoos 
(an  Egyptian  rat) ;  the  blood  of  these  animals  con- 
tains apparently  an  antitoxin.* 

Fontana  f  had  remarked  that  snakes  were  quite 
unaffected  by  the  bite  of  the  viper,  even  when 
inoculated  with  the  venom  hypodermically.  Phy- 
salix  and  Bertrand  t  confirmed  these  statements, 
and  showed  that  the  snake  perfectly  resisted  quan- 
tities of  viper-venom  capable  of  killing  at  least 
20  guinea-pigs.  According  to  these  scientists, 
this  natural  immunity  is  due  to  the  existence  in 
the  blood  of  toxic  principles  analogous  to  those  of 
viper's  venom — principles  that  exist  in  the  labial 
glands  of  the  snake,  and  pass  into  the  blood  and 
the  fluids  via  the  internal  secretions.  These  writers, 
and  also  Calmette,  have  shown  that  the  blood  of 
venomous  serpents  becomes  antitoxic  when  heated. 


*  Compt.  rend,  de  V Acad,  des  Sciences,  cxxi,  p.  745;  Jacodot: 
Arch,  de  Medecine  Navale,  vn,  p.  390. 

t  Traite  sur  le  Venin  de  la  Viper e,  Florence,  1781. 
%  Archives  de  Physiologic,  1894,  p.  423. 


THE   VENOMS.  91 

It  has  been  known  for  a  long  time  that  the 
hedgehog  and  the  mongoos  eat  certain  venomous 
reptiles,  and  eagerly  hunt  for  the  vipers  in  par- 
ticular.     When    the    hedgehog    is    bitten,    which 

happens  quite  often  despite  its  dexterity,  it  resists 
the  viper-venom  quite  well.  Physalix  and  Ber- 
trand  *  have  experimentally  demonstrated  that  the 
hedgehog  withstands  a  dose  of  viper-venom  capable 
of  killing  at  least  40  guinea-pigs.  Levin  f  has 
shown  that  young  individuals  are  less  resistant, 
and  it  is  concluded  from  this,  and  perhaps  incor- 
rectly so,  that  the  immunity  of  the  hedgehog  is 
naturally  acquired,  rather  than  inherent.  Bertrand 
and  Physalix  have  nevertheless  shown  that  on 
heating  the  blood  of  the  hedgehog  to  88°  C.  it 
manifests  an  antitoxic  power  toward  serpent-venom 
in  vitro. 

Artificial  Immunity  toward  Serpent-venom. — 
Immunity  may  be  conferred  upon  every  individual 
by  utilizing  the  method  of  habituation.  This 
fact  was  simultaneously  elicited  by  Calmette, 
Bertrand,  and  Physalix.  To  effect  the  immunity 
these  scientists  prepare  an  antivenomous  serum 
and  inject  it  into  animals,  giving  at  first  very  small 
quantities  of  the  diluted  venom,  and  gradually 
increasing  the  doses,   and  the  periods  intervening 

*  Bull.  Museum  Histoire  Naturelle,  1,  p.  294;  Compt.  rend. 
Soc.  de  Biol.,   1899.  p.   77. 

I  Deutsche  mcd.  Woch.,  1898,  p.  629. 


92  TOXINS  AND    ANTITOXINS. 

between  the  injections.  At  the  end  of  about  two 
months  of  this  treatment,  the  immunity  has  reached 
its  maximum.  Certain  rabbits,  thus  slowly  in- 
oculated, have  been  able  to  withstand  0.04  Gm. 
of  the  venom  of  the  naja  at  a  single  injection; 
such  rabbits  then  yield  a  vaccinal  serum.* 

At  the  Institut  Pasteur  at  Lille  there  is  prepared 
in  this  manner  an  antivenomous  serum  from  the 
horse;  it  is  capable  of  acting  upon  20000  times 
its  own  weight.  This  has  rendered  great  service 
in  the  treatment  of  snake-bites,  particularly  in 
hot  countries,  where  the  accidents  are  of  daily 
occurrence.  In  vitro  it  acts  quite  as  well  pre- 
ventively as  therapeutically.  It  arrests  the  effects 
of  the  naja,  the  horned  ceraste,  the  trigonocepha- 
lus,  the  rattlesnake,  and  of  almost  every  one  of  the 
venomous  serpents  known. 

The  relatively  considerable  immunity  possessed 
by  certain  snake-charmers,  and  which  passes  for  a 
magical  gift,  is  due  to  nothing  else  but  a  natural 
immunity,  acquired  perhaps  by  heredity,  and 
it  always  appears  to  follow  as  a  result  of  a  non- 
fatal snake-bite. 

Venoms  of  Batrachians  and  Saurians.  —  We 
observe  here  a  fundamental  difference  between 
these   poisons   and   those   of   snakes,    as   we   shall 


*  Annal.  de  I'Instit.  Pasteur,   1895,  p.  229;    Compt.  rend,  de 
I' Acad,  des  Sciences,  cxxn,  p.  203. 


THE   VENOMS.  93 

see.     These  latter,  in  fact,  appear  to  owe  all  their 

toxicity  to  true  toxins  which  they  contain,  while 
the  poisons  of  batrachians  and  saurians  arc  chiefly 
composci ]  of  alkaloidal  liases.* 

The  poison  of  toads  and  frogs  (studied  by  Faust, 
Bertrand,  and  Physalix)  is  chiefly  secreted  by  the 
glands  of  the  subcutaneous  tissues  of  these  animals; 
it  lias  hut  a  very  slight  action  on  the  unbroken 
skin,  bu1  ii  rapidly  inflames  the  nasal  and  buccal 
conjunctival  mucosa.  The  poison  is  a  yellowish 
Liquid,  milky  and  viscid,  with  a  waxy  odor  and 
an  insupportahly  hitter  taste.  It  is  strongly  acid 
and  caustic.  When  dried,  the  poison  yields  to 
ether  a  fatty  matter  which,  when  ahsorhed  by  an 
animal,  plunges  the  latter  into  a  coma  that  may 
end  in  death. 

The  residue  insoluble  in  ether  contains  the  non- 
toxic albuminoids,  and  ptomaines,  such  as  methyl- 
carbylamine.t  and  isocyanacetic  acid,  resulting 
from  the  decomposition  of  a  lecithin  that  appears 
to  be  soluble  in  ether. 

To  obtain  this  venom,  Physalix  and  Bertrand  J 
skin  the  toads,  first  chloroformed,  and  dry  the 
skins  in  a  vacuum  over  sulphuric  acid ;  the  skins 
arc  then  cleaned  by  treating  with  carbon  disul- 
phide    to    remove    fatty    matters,    and    the    toxic 

*  Cloez:   Compt.  rend,  de  I' Acad,  des  Sciences,  xxxiv,  p.  592. 
f  Ibid.,  xcvni,  p.  538. 
$Ibid.,  cxxvin,  pp.  45-48. 


94  TOXINS   AND    ANTITOXINS. 

principles  removed  by  means  of  95-per  cent,  alcohol ; 
the  poison  so  obtained,  however,  is  impure.  A 
better  procedure  is  to  express  the  parotid  glands 
which  have  been  placed  in  distilled  water.  Faust 
found  in  this  venom  a  principle  which  he  named 
bufonin.  Physalix  and  Bertrand  isolated  from  it 
also  a  resinoid  substance  soluble  in  alcohol  and  in 
a  large  excess  of  water ;  this  substance,  which  they 
named  bufotaline,  acts  upon  the  heart.  These 
authors  have  also  obtained  another  substance 
which  has  a  paralyzing  action,  and  which  they  have 
named  bufotenin. 

The  poison  of  the  common  toad  acts  as  a  para- 
lyzant upon  the  heart  and  on  the  spinal  marrow  * ; 
that  of  the  common  frog  possesses  similar  properties. 
The  poison  of  the  tritons  is  quite  analogous  to  that 
of  the  toads;  it  contains  a  lecithin  hydrolyzable 
by  water  with  the  formation  of  alanin,  formic  acid, 
and  alpha-isocyanopropionic  acid. 

Zalnosky  f  isolated  from  the  glands  of  the 
skin  of  the  salamander  a  white,  thick,  bitter  and 
alkaline  liquid  poison,  containing  a  highly  poison- 
ous alkaloid,  salamandrine,  or  samandarine,  which 
acts  on  the  brain,  the  medulla,  and  the  spinal  cord, 
and  which  has  the  formula  C54H60N2O5;  it  is  a 
strong  base  and  yields  crystallizable  salts. 


*  P.  Bert:    Compt.  rend,  de  la  Soc.  de  Biologie,  1885,  p.  524. 
|  Bull.  Sqc.  Chim.  [2],  vi,  p.  344. 


THE  VENOMS.  95 

Fish-poisons.*  —  Very  little  accurate  knowl< 
is  extant  regarding  these.  Many  fish  are  poison- 
ous, and  among  them  are  the  synanceia,  found  in 
the  Indian  Ocean  between  the  Netherland  Isles  and 
New  Caledonia;  considerable  numbers  are  found 
in  the  neighborhood  of  the  latter  locality.  These 
fish  arc  provided  with  spiny  rays  which  are  in  direct 
communication  with  a  poisonous  system  having  its 
seat  in  the  dorsal  fin.  The  prick  of  one  of  the 
spiny  rays  of  this  fish  may  under  certain  circum- 
stances result  fatally,  and  in  every  case  it  causes  a 
rapid  and  painful  gangrene. 

From  the  reservoir  the  poison  is  conducted  to 
the  sharp  extremity  of  the  spines  by  a  deep  channel 
with  which  each  spiny  ray  is  provided;  the  animal 
has  26  poison-sacs,  two  for  each  ray,  and  the  sacs 
burst  when  the  corresponding  sting  is  in  any  man- 
ner compressed. 

The  poison  is  an  odorless  liquid  having  a  slight 
styptic  or  acidulous  taste,  and  exhibiting  a  bluish 
fluorescence ;  it  rapidly  becomes  turbid. 

The  wcevers,  which  are  numerous  on  the  shores 
of  the  Mediterranean  Sea,  and  which  are  also  met 
with  in  the  northeastern  portion  of  the  Atlantic 
Ocean,  are  likewise  very  dangerous,  which  explains 
their    popular    names    "  viper-weever,"     "  spider- 

*  Bofford:  These  de  doctoral  en  M6decine — Les  Poissons 
venimeux,  Paris,  1889;  O.  Arcos:  These  de  doctoral — Essais 
sur  les  accidents  causes  par  les  poissons  venimeux.  Paris,  18S7. 


Q6  TOXINS  AND  ANTITOXINS. 

weever,"  etc.  These  fish  are  provided  with  a  double 
set  of  poisonous  apparatus,  the  one  opercular, 
which  is  the  more  dangerous,  and  the  other  dorsal. 
The  opercular  spine  has  a  double  channel  in  con- 
nection with  a  conical  cavity  hollowed  out  in  the 
base  of  the  opercular  bone.  The  bottom  of  this 
cavity  is  provided  with  special  cells  which  secrete  the 
poison.    The  dorsal  glands  have  a  similar  structure. 

The  poison  of  the  weever  is  a  liquid,  limpid  when 
the  fish  is  alive,  and  turbid  when  dead;  it  has 
a  slight  bluish  fluorescence,  is  neutral  in  reaction, 
and  is  coagulated  by  acids  and  bases.  It  acts  as  a 
paralyzant,  its  action  being  exerted  on  the  medulla 
and  spinal  cord;    it  retards  the  heart's  action. 

These  examples  will  suffice;  and  we  will  not 
dilate  further  on  this  subject,  because,  as  already 
stated,  but  little  is  accurately  known  regarding 
the  subject,  and  what  is  known  may  be  summed 
up  as  follows:  Fish-poisons  always  give  rise  to  an 
intense  pain,  frequently  with  motor  paralysis,  fol- 
lowed by  paralysis  of  sensation;  they  affect  the 
heart,  arresting  it  in  diastole;  and  they  are  more 
dangerous  to  fish,  and  cold-blooded  animals  than 
to  mammifers. 

Poisons  of  the  Hymenoptera.* — The  poison  sys- 
tem of  the  bee,  and  of  such  insects  as  the  wasps, 
bumblebees,  etc.,  is  known  to  consist  of  a  hollow 

*  Philouze:  Venin  dcs  Abeilles.  Annates  de  la  Societe  Linn. 
du  Maine-et-Loire,  iv, 


THE   VENl  >MS.  97 

sting  consisting  of  two  sharp  needles  communicat- 
ing with  two  poison-bearing  glands,  and  forming  a 

flexible  tube.  One  of  these  glands  secretes  an  arid 
liquid  (formic  acid);  the  other  secretes  an  alkaline 
fluid. 

The  action  of  the  bee-poison  is  very  often  benign, 
but  there  have  been  cases  where  death  followed 
the  infliction  of  numerous  stings. 

Our  information  regarding  the  poison  of  the 
cantharides  and  flies  is  very  vague  * ;  the  same 
is  true  of  the  poisons  of  various  arachnids,  acarides, 
and  myriapoda.  So  far  as  spiders  are  concerned, 
it  is  known  that  their  poison  is  an  oily  liquid  having 
an  acid  and  bitter  taste,  and  containing  a  toxalbu- 
min  derived  from  the  skin  of  the  insect.  The 
bite  of  the  ordinary  spider  occasions  simply  a 
slight  local  pain,  with  redness;  that  of  the  large 
poisonous  spider,  however,  may  kill  the  larger 
animals,  and  even  man. 

Poison  of  Scorpions.f — This  poison  is  a  colorless, 
acid  liquid,  having  a  higher  specific  gravity 'than 
water,  in  which  liquid  it  is  soluble.  The  famed 
legend  of  the  suicide  of  scorpions  is  well  known  to 
all.  It  is  stated  that  when  the  insect  finds  itself 
in  a  position  where  its  death  is  inevitable,  it  stings 
itself,  and  dies  from  the  effects  of  its  own  poison. 


*  Joyeux-Laffriee:     These  de  doctoral  en   M4decine,  Paris, 
18S3;  P.  Bert:   Compt.  rend,  de  la  Soc.  de  Biol.,  11  [4],  p.  136. 
fCALMETTE:   Annates  de  V Instil.  Pasteur,  x,  p.  232. 


98  TOXINS  AND   ANTITOXINS. 

A  simple  method  has  even  been  described  of  bring- 
ing this  result  about  experimentally  by  surround- 
ing the  insect  with  a  circle  of  fire.  Bounne,  of 
Madras,*  who  has  studied  the  procedure,  has 
demonstrated  its  entire  falsity  by  showing,  first 
of  all,  that  the  insect  dies  from  the  effects  of  the 
excessive  heat,  and  further,  that  the  poison  of  the 
scorpion  is  harmless  to  individuals  of  the  species 
that  furnish  it. 

Metchinkoff  f  has  confirmed  these  facts,  and 
has  moreover  demonstrated  that  the  blood  of  the 
scorpion  possesses  an  undoubted  antitoxic  power 
against  the  poison  of  the  insect. 

The  poison  of  the  scorpion  serves  it  to  kill  the 
insects  which  are  its  prey.  Frogs  and  birds  stung 
by  the  scorpion  also  generally  die.  A  dose  of 
0.0005  Gm.  kills  a  guinea-pig  in  less  than  one  hour; 
and  according  to  Calmette  t  less  than  0.0005  wiu 
kill  a  white  mouse  in  two  hours.  Oxidizers  destroy 
the  toxicity  of  the  poison.  Guinea-pigs  immu- 
nized against  the  poison  of  the  scorpion  resist  per- 
fectly very  large  doses  of  the  poison. 

Poisonous  Blood  and  Serums. — It  is  an  almost 
general  fact  that  the  blood  and  blood  serum  of 
batrachians,  eels,  lampreys,  snakes  (even  non- 
poisonous  ones),  and  hedgehogs  are  very  poisonous. 

*  Proceedings  of  the  Royal  Society,  xlii,  p.  17. 

t  Metchnikoff:    L'lmmunite,  p.  344. 

J  Calmette:  Annal.  de  I'lnstit.  Pasteur,  x,  p.  232. 


THE  VENOMS.  99 

Mosso  has  found  in  the  Mood  scrum  of  the 
lamprey  a  toxin  possessing  a  strong  hemolytic 
power,  and  which  he  has  named  ichthyotoxin.  0.5 
Cc.  of  this  serum  injected  into  a  dog  kills  it  in 
a  few  minutes.  He  also  observed,  in  1888,  that 
the  blood  of  the  eel,  in  like  dose,  kills  a  dog 
almost  immediately,  and  that  the  blood  contains 
an  ichthyotoxin  analogous  to  that  of  the 
lamprey. 

This  substance,  which  appears  to  be  closely 
allied  to  the  sero-albumin  of  the  blood,  has  a 
phosphorus-like,  sharp,  and  burning  taste.  By  diges- 
tion it  loses  its  toxicity,  as  well  as  by  heating  at 
68°  to  700  C.  It  is  easily  obtained  by  precipitating 
with  ammonium  sulphate  the  serum  of  eels,  and 
dialyzing  the  precipitate  dissolved  in  water.  The 
power  of  this  substance  is  almost  as  great  as  that 
of  the  cobra  poison,  0.002  Gm.  being  instantly 
fatal  per  kilo  of  dog. 

The  blood  of  snakes  is  likewise  very  toxic;  the 
same  is  true  of  the  blood  of  the  viper,  as  0.02  Cc. 
will  kill  a  guinea-pig  in  two  hours.  All  these 
bloods  lose  their  toxicity  when  heated  above  700  C. 
The  serum  of  the  hedgehog  is  peculiar  in  this 
respect;  when  heated  at  380  C.  for  fifteen  minutes 
it  loses  its  toxicity,  but  it  then  possesses  an  immu- 
nizing power  against  the  poisons. 

The  subject  possesses  great  interest,  because  it 
was  in  studying  these  immunizing  properties  that 


loo  TOXINS  AND   ANTITOXINS. 

Camus  and  Gley,*  and  later  on  Kossel  f  and 
Tchisto  witch,  |  discovered  the  first  anticy  to  toxin,  § 
which  they  obtained  by  treating  the  animals  with 
increasing  quantities  of  the  serum  of  eels.  On 
mixing  the  antitoxic  serum  of  these  animals  in 
vitro  with  the  red  blood-corpuscles  of  the  species 
furnishing  the  serum  and  of  the  hemolytic  serum 
of  eels,  it  is  found  that  the  blood-corpuscles  kept 
quite  well. 

As  to  the  blood  of  the  hedgehog,  we  have  already 
seen  that  Physalix  and  Bertrand  have  shown  that 
it  may  be  a  counter-poison  towards  serpent-venom 
under  certain  conditions.  In  its  normal  condition 
it  is  highly  toxic. 

Poisonous  Meats. — It  is  particularly  among  the 
fish  that  we  find  these  normally  present,  and  it  is 

*  Archives  internal,  de  Pharmacodynamic,  in  and  iv. 

f  Berliner  Klin.  Wcchenschr.,  1895,  No.  7. 

J  Annal.  de  I'Instit.  Pasteur,  xin,  p.  406. 

§  The  name  "cytases"  or  "alexins"  has  been  given  to 
hemolyzing  diastatic  substances  which  are  found  in  certain 
serums.  It  has  been  known  for  a  long  time  that  the  serum 
of  the  blood  of  many  animals  destroys  the  red  blood-corpuscles 
of  other  and  different  species.  The  chemical  composition  of 
these  cytases  or  alexins  is  not  yet  definitely  known,  but  the 
substances  rank  among  the  albuminoids;  they  are  destroyed 
by  a  temperature  of  550  to  560  C,  and  act  only  in  saline 
solutions  (Ehrlich  and  Morgenroth,  Berlin.  Klin.  Woch.,  pp. 
6  and  481).  The  cytases  or  alexins,  which  will  be  studied 
in  another  volume  of  this  collection,  and  which  will  discuss 
the  active  principles  of  the  immunizing  serums,  constitute  one 
of  the  numerous  soluble  intraleucocytary  ferments,  and  they 
pass  into  the  serous  liquids  of  the  organism  only  as  the  result 
of  a  rupture  of  or  injury  to  the  phagocytes. 


'[  iik  VENOMS.  101 

a  singular  fact  that,  for  a  given  species,  the  toxicity 

frequently  depends  upon  the  period  of  the  year. 
Thus,  at  the  period  of  spawning,  certain  fish  may 
be  extremely  poisonous,  or,  on  the  contrary,  may 
entirely  cease  to  be  so.  The  anchovy  ballassa 
from  the  shores  of  India  occasions  death  even  in 
very  small  quantity;  the  poisonous  meltite  of  the 
same  seas  causes  violent  vomiting;  the  fugu  of 
the  Japanese  seas  possesses  an  extreme  poison- 
ousness  at  the  spawning  period,  while,  on  the  con- 
trary, it  is  perfectly  innocuous  at  all  other  periods. 

Numerous  cases  of  poisoning  have  been  chronicled 
every  year  by  the  journals,  due  to  the  ingestion 
of  mussels ;  in  the  flesh  of  these  crustacese  is  found 
a  dangerous  toxin,  melhylotoxin.  The  flesh  of 
oysters  is  also  unwholesome  at  the  spawning  period. 

The  toxic  symptoms  caused  by  these  animals 
become  apparent  in  not  less  than  twenty-four 
hours  after  ingestion.  The  poisoning  due  to  these 
fresh  meats  must  not,  however,  be  confounded 
with  that  caused  by  tainted  or  spoiled  meats. 


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*  Treatise  on  the  Military  Law  of  United  States 8vo,    7  00 

Sheep,  7  50 

De  Brack's  Cavalry  Outposts  Duties.     (Carr.) 24010,  morocco,  2  00 

Dietz's  Soldier's  First  Aid  Handbook i6mo,  morocco,  1  25 

*  Dredge's  Modern  French  Artillery 4to,  half  morocco,  15  00 

Durand's  Resistance  and  Propulsion  of  Ships 8vo,  5  00 

*  Dyer's  Handbook  of  Light  Artillery i2mo,  3  00 

Eissler's  Modern  High  Explosives 8vo,  4  00 

*  Fiebeger's  Text-book  on  Field  Fortification Small  8vo,  2  00 

Hamilton's  The  Gunner's  Catechism i8mo,  1  00 

*  Hoff's  Elementary  Naval  Tactics 8vo,  1  50 

Ingalls's  Handbook  of  Problems  in  Direct  Fire 8vo,  4  00 

*  "■■   Ballistic  Tables 8vo,    1  50 

*  Lyons's  Treatise  on  Electromagnetic  Phenomena.  Vols.  I.  and  H. .  8vo,  each,  6  00 

*  Mahan's  Permanent  Fortifications.    (Mercur.) 8vo,  half  morocco,  7  50 

Manual  for  Courts-martial i6mo,  morocco,  1  50 

*  Mercur's  Attack  of  Fortified  Places i2mo,  2  00 

*  Elements  of  the  Art  of  War 8vo,  4  00 

Metcalf's  Cost  of  Manufactures — And  the  Administration  of  Workshops.  .8vo,  5  00 

*  Ordnance  and  Gunnery.     2  vols nmo,  5  00 

Murray's  Infantry  Drill  Regulations i8mo,  paper,  10 

Nixon's  Adjutants'  Manual 24010,  1  00 

Peabody's  Naval  Architecture 8vo,  7  50 

s 


*  Phelps's  Practical  Marine  Surveying 8vo,  2  50 

Powell's  Army  Officer's  Examiner umo,  4  00 

Sharpe's  Art  of  Subsisting  Armies  in  War i8mo.  morocco,  1   50 

*  Walke's  Lectures  on  Explosives 8vo,  4  00 

*  Wheeler's  Siege  Operations  and  Military  Mining 8vo,  2  00 

Winthrop's  Abridgment  of  Military  Law 12 mo,  2   50 

WoodhulPs  Notes  on  Military  Hygiene i6mo,  1   50 

Young's  Simple  Elements  of  Navigation i6mo,  morocco,  1   00 

Second  Edition,  Enlarged  and  Revised i6mo,  morocco,  2  00 

ASSAYING. 
Fletcher's  Practical  Instructions  r.  Quantitative  Assaying  with  the  Blowpipe. 

i2mo,  morocco,     1   50 

Furman's  Manual  of  Practical  Assaying 8vo, 

Lodge's  Notes  on  Assaying  and  Metallurgical  Laboratory  Experiments.  .  .   8vo, 

Miller's  Manual  of  Assaying i2mo, 

O'DriscolPs  Notes  on  the  Treatment  of  Gold  Ores 8vo, 

Ricketts  and  Miller's  Notes  on  Assaying 8vo, 

Ulke's  Modern  Electrolytic  Copper  Refining 8vo, 

Wilson's  Cyanide  Processes i2mo, 

Chlorination  Process i2mo, 

ASTRONOMY. 

Comstock's  Field  Astronomy  for  Engineers 8vo, 

Craig's  Azimuth 4to, 

Doolittle's  Treatise  on  Practical  Astronomy 8vo, 

Gore's  Elements  of  Geodesy 8vo, 

Hayford's  Text-book  of  Geodetic  Astronomy 8vo, 

Merriman's  Elements  of  Precise  Surveying  and  Geodesy 8vo, 

*  Michie  and  Harlow's  Practical  Astronomy 8vo, 

*  White's  Elements  of  Theoretical  and  Descriptive  Astronomy i2mo, 

BOTANY. 

Davenport's  Statistical  Methods,  with  Special  Reference  to  Biological  Variation. 

i6mo,  morocco,  1  25 

Thome'  and  Bennett's  Structural  and  Physiological  Botany i6mo,  2  25 

Westermaier's  Compendium  of  General  Botany.     (Schneider.) 8vo,  2  00 

CHEMISTRY. 

Adriance's  Laboratory  Calculations  and  Specific  Gravity  Tables i2mo,     1   25 

Allen's  Tables  for  Iron  Analysis 8vo, 

Arnold's  Compendium  of  Chemistry.     (Mandel.) Small  8vo, 

Austen's  Notes  for  Chemical  Students i2mo, 

Bernadou's  Smokeless  Powder. — Nitro-cellulose,  and  Theory  of  the  Cellulose 

Molecule i2mo, 

Bolton's  Quantitative  Analysis 8vo, 

*  Browning's  Introduction  to  the  Rarer  Elements 8vo, 

Brush  and  Penfield's  Manual  of  Determinative  Mineralogy 8vo, 

Classen's  Quantitative  Chemical  Analysis  by  Electrolysis.    (Boltwood. ).   8vo, 
Cohn's  Indicators  and  Test-papers 1 2 mo, 

Tests  and  Reagents 8vo, 

Crafts's  Short  Course  in  Qualitative  Chemical  Analysis.   (Schaeffer.). .  .  i2mo, 
Dolezalek's   Theory  of  the   Lead  Accumulator   (Storage   Battery).         (Von 

Ende.) i2mo, 

Drechsel's  Chemical  Reactions.     (Merrill.  1 i2mo, 

Duhem's  Thermodynamics  and  Chemistry.     1  Burgess. ) 8vo, 

Eissler's  Modern  High  Explosives 8vo, 

Effront's  Enzymes  and  their  Applications.     (Prescott.i 8vo, 

Ecdmann's  Introduction  to  Chemical  Preparations.     (Dunlap.) i2mo, 

3 


3 

00 

3 

00 

1 

00 

2 

00 

3 

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So 

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50 

2 

90 

3 

So 

4 

00 

2 

50 

3 

00 

2 

SP 

3 

00 

2 

00 

3 

00 

3 

50 

1 

5'J 

2 

50 

1 

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1 

50 

4 

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3 

00 

2 

DO 

3 

DO 

1 

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2 

50 

1 

25 

4 

00 

4 

00 

3 

00 

1 

-5 

Fletcher's  Practical  Instructions  in  Quantitative  Assaying  with  the  Blowpipe. 

i2mo,  morocco,     i  50 

Fowler's  Sewage  Works  Analyses I2m0>  2  °° 

Fresenius's  Manual  of  Qualitative  Chemical  Analysis.     (Wells.) 8vo,  5  00 

Manual  of  Qualitative  Chemical  Analysis.  Part  I.  Descriptive.  (Wells.)  8vo,  3  oa 
System   of    Instruction    in    Quantitative    Chemical   Analysis.      (Cohn.) 

2  vols 8vo'  I2  5° 

Fuertes's  Water  and  Public  Health. ... iznio,  1  50 

Furman's  Manual  of  Practical  Assaying 8vo,  3  00 

*  German's  Exercises  in  Physical  Chemistry i2mo,.    2  00 

Gill's  Gas  and  Fuel  Analysis  for  Engineers i2mo,  1  25 

Grotenfelt's  Principles  of  Modern  Dairy  Practice.     (Woll.) izmo,  2  00 

Hammarsten's  Text-book  of  Physiological  Chemistry.     (Mandel.) 8vo,  4  00 

Helm's  Principles  of  Mathematical  Chemistry.     (Morgan.) i2mo,  1  50 

Hering's  Ready  Reference  Tables  (Conversion  Factors) i6mo,  morocco,  2  50 

Hind's  Inorganic  Chemistry - 8vo'  3  00 

*  Laboratory  Manual  for  Students 12010,        75 

HoDeman's  Text-book  of  Inorganic  Chemistry.     (Cooper.) 8vo,    2  50 

Text-book  of  Organic  Chemistry.     (Walker  and  Mott.) •  -8vo,  2  50 

*  Laboratory  Manual  of  Organic  Chemistry.     (Walker.) I2mc-  I  00 

Hopkins's  Oil-chemists'  Handbook 8vo>  3  00 

Tackson's  Directions  for  Laboratory  Work  in  Physiological  Chemistry.  .8vo,  1  25 

keep's  Cast  Iron 8v0'  2  5° 

Ladd's  Manual  of  Quantitative  Chemical  Analysis I2mo'  J  °° 

Landauer's  Spectrum  Analysis.     (Tingle  ) •■•••■  -8v0>  3  00 

*  Langworthy  and   Austen.        The  Occurrence   of  Aluminium  in  Vegetable 

Products,  Animal  Products,  and  Natural  Waters 8vo,  2  00 

Xassar-Cohn's  Practical  Urinary  Analysis.     (Lorenz.) I2mo'  r  o0 

Application  of  Some   General  Reactions   to   Investigations  in  Organic 

Chemistry.     (Tingle.) •••••■• 12™' 

Leach's  The  Inspection  and  Analysis  of  Food  with  Special  Reference  to  State 

Control ; ■ '  -8v°'  7  5° 

Lob's  Electrolysis  and  Electrosynthesis  of  Organic  Compounds.  (Lorenz.).i2mo,  1  00 

Lodge's  Notes  on  Assaying  and  Metallurgical  Laboratory  Experiments.  ..  .8vo,  3  00 

Lunge's  Techno-chemical  Analysis.     (Cohn.) i2m0»  *  °° 

Mandel's  Handbook  for  Bio-chemical  Laboratory  ..............._.,-..  "mo,  50 

*  Martin's  Laboratory  Guide  to  QuaUtative  Analysis  with  the  Blowpipe     lamo  60 
Mason's  Water-supply.     (Considered  Principally  from  a  Sanitary  Standpoint  ) 

-^.  •  A   L  OVOl  tX.         \J\J 

3d  Edition,  Rewritten ■  •  •  ■ * 

Examination  of  Water.     (Chemical  and  Bacteriological.) i2mo,  1  25 

Matthew's  The  Textile  Fibres '."'"'   V°' 

M^eTs  Determination  of  Radicles  in  Carbon  Compounds.     (Tingle.),  .nmo,  1  00 

Miller's  Manual  of  Assaying * ' 

Mixter's  Elementary  Text-book  of  Chemistry ™'  \  S 

Morgan's  Outline  of  Theory  of  Solution  and  its  Results »mo,  1  00 

Elements  of  Physical  Chemistry • "      ' 

Morse's  Calculations  used  in  Cane-sugar  Factories .  .1  mo,  morocco,  1  50 

Mulhken's  General  Method  for  the  Identification  of  Pure  Organic  founds.  ^  ^ 

O'Brine's  Laboratory  Guide  in  Chemical  Analysis «vo,    2  00 

O'DriscoU's  Notes  on  the  Treatment  of  Gold  Ores.  . .      • ■  .»vo,    2  00 

Ostwald's  Conversations  on  Chemistry.  Part  One.  Ramsey  ).  .  »mo. 
Ostwald's  Conversations  on  Chemistry.  Part  Two.  (Turnbull.).  ^^-> 
"penfield's  Notes  on  Determinative  Mineralogy  and  Record  of  Mmeral £>£        ^ 

Pictet's  The  Alkaloids  and  their  Chemical  Constitution      (Biddle.)  .  .  .      8vo,    5  00 

Pinner's  Introduction  to  Organic  Chemistry.     (Austen.) «mo.    1  50 

Poole's  Calorific  Power  of  Fuels •  •  • ■  •_• ;  •  ■  ■  •  •  ■ ' '       ' 

Prescott  and  Winslow's  Elements  of  Water  Bacteriology,  with  Spec  a  Refer- 

ence  to  Sanitary  Water  Analysis 

4 


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2 

50 

I 

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3 

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2 

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*  Reisig's  Guide  to  Piece-dyeing 8vo,  25  00 

Richards  and  Woodman's  Air,  Water,  and  Food  from  a  Sanitary  Standpoint  8vo,    2  00 
Richards's  Cost  of  Living  as  Modified  by  Sanitury  Science 121110,     1  00 

Cost  of  Food,  a  Study  in  Dietaries umo,     1  00 

*  Richards  and  Williams's  The  Dietary  Computer 8vo,     1  50 

Rickctts  and  Russell's  Skeleton  Notes  upon   Inorganic   Chemistry.       Part  I. 

Non-metallic  Elements.) 8vo,  morocco,         75 

Ricketts  and  Miller's  Notes  on  Assaying 8vo,    3  00 

Rideal's  Sewage  and  the  Bacterial  Purificat  on  of  Sewage 8vo,    3  50 

Disinfection  and  the  Preservation  of  Food 8vo,     .1   00 

Rigg's  Elementary  Manual  for  the  Chemical  Laboratory 8vo,     1   25 

Rostoski's  Serum  Diagnosis.     (Bolduan.) umo,     1   00 

Ruddiman's  Incompatibilities  in  Prescriptions 8vo,    2  00 

Sabin's  Industrial  and  Artistic  Technology  of  Paints  and  Varnish 8vo,    3  00 

Salkowski's  Physiological  and  Pathological  Chemistry.     (Orndorff.) 8vo, 

Schimpf's  Text-book  of  Volumetric  Analysis i2mo, 

Essentials  of  Volumetric  Analysis i2mo, 

Spencer's  Handbook  for  Chemists  of  Beet-sugar  Houses i6mo,  morocco, 

Handbook  for  Sugar  Manufacturers  and  their  Chemists.  .i6mo,  morocco, 
Stockbridge's  Rocks  and  Soils 8vo, 

*  Tillman's  Elementary  Lessons  in  Heat 8vo, 

*  Descriptive  General  Chemistry 8vo, 

Treadwell's  Qualitative  Analysis.     (Hall.) 8vo. 

Quantitative  Analysis.     (Hall.) 8vo, 

Turneaure  and  Russell's  Public  Water-supplies 8vo, 

Van  Deventer's  Physical  Chemistry  for  Beginners.     (Boltwood.) i2mo,     1   50 

*  Walke's  Lectures  on  Explosives 8vo,    4  00 

Washington's  Manual  of  the  Chemical  Analysis  of  Rocks 8vo,    2  00 

Wassermann's  Immune  Sera :  Hemolysins,  Cytotoxins,  and  Precipitins.    ( Bol- 
duan.)   i2mo,     1  00 

Well's  Laboratory  Guide  in  Qualitative  Chemical  Analysis 8vo,     1  50 

Short  Course  in  Inorganic  Qualitative  Chemical  Analysis  for  Engineering 

Students i2mo,     I  50 

Text-book  of  Chemical  Arithmetic.     (In  press.) 

Whipple's  Microscopy  of  Drinking-water 8vo,    3  50 

Wilson's  Cyanide  Processes i2mo,     1  50 

Chlorination  Process i2mo,     1  50 

Wulling's    Elementary    Course    in  Inorganic,  Pharmaceutical,  and  Medical 

Chemistry umo,    2  00 

CIVIL  ENGINEERING. 
BRIDGES    AND    ROOFS.       HYDRAULICS.       MATERIALS   OF    ENGINEERING. 
RAILWAY  ENGINEERING. 

Baker's  Engineers'  Surveying  Instruments i2mo,  3  00 

Bixby's  Graphical  Computing  Table Paper  XO&X  24i  inches.  25 

**  Burr's  Ancient  and  Modern  Engineering  and  the  Isthmian  Canal.     (Postage, 

27  cents  additional.) 8vo,  3  50 

Comstock's  Field  Astronomy  for  Engineers 8vo,  2  50 

Davis's  Elevation  and  Stadia  Tables 8vo,  1  00 

Elliott's  Engineering  for  Land  Drainage i2mo,  1  50 

Practical  Farm  Drainage i2mo,  1  00 

Fiebeger's  Treatise  on  Civil  Engineering.     (In  press.) 

Folwell's  Sewerage.     (Designing  and  Maintenance.  1 8vo,  3  00 

Freitag's  Architectural  Engineering.     2d  Edition,  Rewritten 8vo,  3  50 

French  and  Ives's  Stereotomy 8vo,  2  50 

Goodhue's  Municipal  Improvements i2mo,  1  75 

Goodrich's  Economic  Disposal  of  Towns'  Refuse 8vo,  3  50 

Gore's  Elements  of  Geodesy 8vo,  2  50 

Hayford's  Text-book  of  Geodetic  Astronomy 8vo,  3  00 

Hering's  Ready  Reference  Tables  (Conversion  Factors'* i6mo,  morocco,  2  50 

5 


7 

50 

5 

00 

3 

50 

i 

50 

2 

50 

2 

00 

5 

oo 

5 

oo 

6 

oo 

6 

50 

5 

00 

5 

50 

3 

00 

Howe's  Retaining  Walls  for  Earth i2mo,    1  2.5 

Johnson's  (J.  B.)  Theory  and  Practice  of  Surveying Small  8vo,    4  00 

Johnson's  (L.  J.)  Statics  by  Algebraic  and  Graphic  Methods 8vo,    2  00 

Laplace's  Philosophical  Essay  on  Probabilities.     (Truscott  and  Emory.) .  i2mo,    2  00 
Mahan's  Treatise  on  Civil  Engineering.     (1873.)     (Wood.) 8vo,    5  00 

*  Descriptive  Geometry 8vo,    1  50 

Merriman's  Elements  of  Precise  Surveying  and  Geodesy 8vo,    2  50 

Elements  of  Sanitary  Engineering 8vo,    2  00 

Merriman  and  Brooks's  Handbook  for  Surveyors i6mo-,  morocco,    2  00 

Nugent's  Plane  Surveying 8vo,    3  50 

Ogden's  Sewer  Design i2mo,    2  00 

Patton's  Treatise  on  Civil  Engineering 8vo  half  leather, 

Reed's  Topographical  Drawing  and  Sketching 4to, 

Rideal's  Sewage  and  the  Bacterial  Purification  of  Sewage 8vo, 

Siebert  and  Biggin's  Modern  Stone-cutting  and  Masonry 8vo, 

Smith's  Manual  of  Topographical  Drawing.     (McMillan.) 8vo, 

Sondericker's  Graphic  Statics,  with  Applications  to  Trusses,  Beams,  and  Arches. 

8vo, 
Taylor  and  Thompson's  Treatise  on  Concrete,  Plain  and  Reinforced 8vo, 

*  Trautwine's  Civil  Engineer's  Pocket-book i6mo,  morocco, 

Wait's  Engineering  and  Architectural  Jurisprudence 8vo, 

Sheep, 
Law  of  Operations  Preliminary  to  Construction  in  Engineering  and  Archi- 
tecture  8vo, 

Sheep, 

Law  of  Contracts 8vo, 

Warren's  Stereotomy — Problems  in  Stone-cutting 8vo,    2  50 

Webb's  Problems  in  the  Use  and  Adjustment  of  Engineering  Instruments. 

i6mo,  morocco,     1   25 

*  Wheeler  s  Elementary  Course  of  Civil  Engineering 8vo,    4  00 

Wilson's  Topographic  Surveying 8vo,    3  50 

BRIDGES  AND   ROOFS. 

Boiler's  Practical  Treatise  on  the  Construction  of  Iron  Highway  Bridges.    8vo,    2  00 

*  Thames  River  Bridge 4to,  paper,    5  00 

Burr's  Course  on  the  Stresses  in  Bridges  and  Roof  Trusses,  Arched  Ribs,  and 

Suspension  Bridges 8vo,  3  50 

Burr  and  Falk's  Influence  Lines  for  Bridge  and  Roof  Computations.  .  .  .  8vo,  3  00 

Du  Bois's  Mechanics  of  Engineering.     Vol.  II Small  4to,  10  00 

Foster's  Treatise  on  Wooden  Trestle  Bridges 4to,  5  00 

Fowler's  Ordinary  Foundations 8vo,  3  50 

Greene's  Roof  Trusses 8vo,  1  25 

Bridge  Trusses 8vo,  2  50 

Arches  in  Wood,  Iron,  and  Stone 8vo,  2  50 

Howe's  Treatise  on  Arches 8vo,  4  00 

Design  of  Simple  Roof-trusses  in  Wood  and  Steel 8vo,  2  00 

Johnson,  Bryan,  and  Turneaure's  Theory  and  Practice  in  the  Designing  of 

Modern  Framed  Structures Small  410,  10  00 

Merriman  and  J acoby's  Text-book  on  Roofs  and  Bridges : 

Part  I.     Stresses  in  Simple  Trusses 8vo,  2  50 

Part  H.     Graphic  Statics 8vo,  2  50 

Part  HI.     Bridge  Design 8vo,  2  50 

Part  TV.     Higher  Structures 8vo,  2  50 

Morison's  Memphis  Bridge 4to,  10  00 

Waddell's  De  Pontibus,  a  Pocket-book  for  Bridge  Engineers.  .  i6mo,  morocco,  3  00 

Specifications  for  Steel  Bridges i2mo,  1  25 

Wood's  Treatise  on  the  Theory  of  the  Construction  of  Bridges  and  Roofs .  . 8vo,  2  c^ 
Wright's  Designing  of  Draw-spans : 

Part  I.     Plate-girder  Draws 8vo,  2  50 

Part  II.     Riveted-truss  and  Pin-connected  Long-span  Draws 8vo,  2  50 

Two  parts  in  one  volume 8vo,  3  5« 

6 


HYDRAbLICS. 

Bazin's  Experiments  upon  the  Contraction  of  the  Liquid  Vein  Issuing  from 

an  Orifice.     (Trautwine.) 8vo,  2  oo 

Bovey's  Treatise  on  Hydraulics 8vo,  5  00 

Church's  Mechanics  of  Engineering 8vo,  6  00 

Diagrams  of  Mean  Velocity  of  Water  in  Open  Channels    paper,  1  50 

Coffin's  Graphical  Solution  of  Hydraulic  Problems iomo,  morocco,  2  50 

Flather's  Dynamometers,  and  the  Measurement  of  Power i2mo,  3  00 

Folwell's  Water-supply  Engineering 8vo,  4  00 

Frizell's  Water-power 8vo,  5  00 

Fuertes's  Water  and  Public  Health nrao,  1  50 

Water-filtration  Works i2mo,  2  50 

Ganguillet  and  Kutter's  General  Formula  for  the  Uniform  Flow  of  Water  in 

Rivers  and  Other  Channels.     ^Hering  and  Trau    vine.) 8vo  4  00 

Hazen's  Filtration  of  Public  Water-supply 8vo,  3  00 

Hazlehurst's  Towers  and  Tanks  for  Water-works 8vo,  2  50 

Herschel's  115  Experiments  on  the  Carrying  Capacity  of  Large,  Riveted,  Metal 

Conduits 8vo,  2  00 

Mason's  Water-supply.     (Considered  Principally  from  a  Sanitary  Standpoint.  I 

8vo,  4  00 

Merriman's  Treatise  on  Hydraulics 8vo,  5  00 

*  Michie's  Elements  of  Analytical  Mechanics 8vo,  4  00 

Schuyler's   Reservoirs   for   Irrigation,   Water-power,   and   Domestic   Water- 
supply Large  8vo,  5  00 

**  Thomas  and  Watt's  Improvement  of  Rivers.     (Post.,  44c.  additional. ).4to,  6  00 

Turneaure  and  Russell's  Public  Water-supplies 8vo,  5  00 

Wegmann's  Design  and  Construction  of  Dams 4to,  5  00 

Water-supply  of  the  City  of  New  York  from  1658  to  1895 4to,  10  00 

Wilson's  Irrigation  Engineering Small  8vo,  4  00 

Wolff's  Windmill  as  a  Prime  Mover 8vo,  3  00 

Wood's  Turbines 8vo,  2  50 

Elements  of  Analytical  Mechanics 8vo,  3  00 

MATERIALS   OF   ENGINEERING. 

Baker's  Treatise  on  Masonry  Construction •  .  .  .  .8vo,  5  00 

Roads  and  Pavements 8vo,  5  00 

Black's  United  States  Public  Works Oblong  4to>  5  00 

Bovey's  Strength  of  Materials  and  Theory  of  Structures 8vo,  7  50 

Burr's  Elasticity  and  Resistance  of  the  Materials  of  Engineering 8vo,  7  50 

Byrne's  Highway  Construction 8vo,  5  00 

Inspection  of  the  Materials  and  Workmanship  Employed  in  Construction. 

i6mo,  3  00 

Church's  Mechanics  of  Engineering 8vo,  6  00 

Du  Bois's  Mechanics  of  Engineering.     VoL  I Small  4to,  7  50 

Johnson's  Materials  of  Construction Large  8vo,  6  00 

Fowler's  Ordinary  Foundations 8vo,  3  50 

Keep's  Cast  Iron 8vo,  2  50 

Lanza's  Applied  Mechanics 8vo,  7  50 

Marten's  Handbook  on  Testing  Materials.     (Henning.  ">     2  vols 8vo,  7  50 

Merrill's  Stones  for  Building  and  Decoration 8vo,  5  00 

Merriman's  Text-book  on  the  Mechanics  of  Materials 8vo,  4  00 

Strength  of  Materials i2mo,  1  00 

Metcalf's  Steel.     A  Manual  for  Steel-users i2mo,  2  00 

Patton's  Practical  Treatise  on  Foundations .. 8vo,  5  oe 

Richardson's  Modern  Asphalt  Pavements 8vo,  3  00 

Richey's  Handbook  for  Superintendents  of  Construction IOmo,  mor.,  4  00 

Rockwell's  Roads  and  Pavements  in  France i2mo,  1  35 

7 


Sabin's  Industrial  and  Artistic  Technology  of  Paints  and  Varnish 8vo,  3  00 

Smith's  Materials  of  Machines nmo,  1  00 

Snow's  Principal  Species  of  Wood , 8vo,  3  50 

Spalding's  Hydraulic  Cement umo,  2  00 

Text-book  on  Roads  and  Pavements nmo,  2  00 

Taylor  and  Thompson's  Treatise  on  Concrete,  Plain  and  Reinforced 8vo,  5  00 

Thurston's  Materials  of  Engineering.     3  Parts 8vo,  8  00 

Part  I.     Non-metallic  Materials  of  Engineering  and  Metallurgy 8vo,  2  00 

Part  II.     Iron  and  Steel 8vo,  3  50 

Part  III.     A  Treatise  on  Brasses,  Bronzes,  and  Other  Alloys  and  their 

Constituents 8vo,  2  50 

Thurston's  Text-book  of  the  Materials  of  Construction 8vo,  5  00 

Tillson's  Street  Pavements  and  Paving  Materials 8vo,  4  00 

Waddell's  De  Pontibus.    (A  Pocket-book  for  Bridge  Engineers.).  .  i6mo,  mor.,  3  00 

Specifications  for  Steel  Bridges i2mo,  1  25 

Wood's  (De  V.)  Treatise  on  the  Resistance  of  Materials,  and  an  Appendix  on 

the  Preservation  of  Timber 8vo,  2  00 

Wood's  (De  V.)  Elements  of  Analytical  Mechanics 8vo,  3  00 

Wood's  (M.  P.)  Rustless  Coatings:    Corrosion  and  Electrolysis  of  Iron  and 

Steel 8vo,  4  00 

RAILWAY  ENGINEERING. 

Andrew's  Handbook  for  Street  Railway  Engineers 3x5  inches,  morocco,  1  25 

Berg's  Buildings  and  Structures  of  American  Railroads 4to,  5  00 

Brook's  Handbook  of  Street  Railroad  Location i6mo,  morocco,  1  50 

Butt's  Civil  Engineer's  Field-book i6mo,  morocco,  2  50 

CrandalPs  Transition  Curve i6mo,  morocco,  1  50 

Railway  and  Other  Earthwork  Tables 8vo,  1  50 

Dawson's  "Engineering"  and  Electric  Traction  Pocket-book.  .  i6mo,  morocco,  5  00 

Dredge's  History  of  the  Pennsylvania  Railroad:   (1879) Paper,  5  00 

*  Drinker's  Tunnelling,  Explosive  Compounds,  and  Rock  Drills. 4to,  half  mor.,  25  o» 

Fisher's  Table  of  Cubic  Yards Cardboard,  25 

Godwin's  Railroad  Engineers'  Field-book  and  Explorers'  Guide.  .  .  i6mo,  mor.,  2  50 

Howard's  Transition  Curve  Field-book i6mo,  morocco,  1  50 

Hudson's  Tables  for  Calculating  the  Cubic  Contents  of  Excavations  and  Em- 
bankments  8vo,  1  00 

Molitor  and  Beard's  Manual  for  Resident  Engineers i6mo,  1  00 

Nagle's  Field  Manual  for  Railroad  Engineers i6mo,  morocco,  3  00 

Philbrick's  Field  Manual  for  Engineers i6mo,  morocco,  3  00 

Searles's  Field  Engineering i6mo,  morocco,  3  00 

Railroad  Spiral i6mo,  morocco,  1  50 

Taylor's  Prismoidal  Formulae  and  Earthwork 8vo,  1  50 

*  Trautwine's  Method  of  Calculating  the  Cube  Contents  of  Excavations  and 

Embankments  by  the  Aid  of  Diagrams 8vo,  2  00 

The  Field  Practice  of  Laying  Out  Circular  Curves  for  Railroads. 

i2mo,  morocco,  2  50 

Cross-section  Sheet Paper,  25 

Webb's  Railroad  Construction i6mo,  morocco,  5  00 

Wellington's  Economic  Theory  of  the  Location  of  Railways Small  8vo,  5  00 

DRAWING. 

Barr's  Kinematics  of  Machinery 8vo,    2  50 

*  Bartlett's  Mechanical  Drawing 8vo,    3  00 

*  "                    "                    "        Abridged  Ed 8vo,  150 

Coolidge's  Manual  of  Drawing 8vo,  paper  1  00 

Coolidge  and  Freeman's  Elements  of  General  Drafting  for  Mechanical  Engi- 
neers  Oblong  4to,  2  50 

Dudley's  Kinematics  of  Machines 8vo,    4  00 

Emch's  Introduction  to  Projective  Geometry  and  its  Applications 8vo.    2  50 


Sill's  Text-book  on  Shades  and  Shadows,  and  Perspective 8vo, 

Jamison's  Elements  of  Mechanical  Drawing 8vo, 

Jones's  Machine  Design: 

Part  I.     Kinematics  of  Machinery 8vo, 

Part  II.     Form,  Strength,  and  Proportions  of  Parts 8vo, 

MacCord's  Elements  of  Descriptive  Geometry 8vo, 

Kinematics;   or.  Practical  Mechanism 8vo, 

Mechanical  Drawing 4to, 

Velocity  Diagrams 8vo, 

*  Mahan's  Descriptive  Geometry  and  Stone-cutting 8vo, 

Industrial  Drawing.     (Thompson.) 8vo, 

Moyer's  Descriptive  Geometry 8vo, 

Reed's  Topographical  Drawing  and  Sketching 4to, 

Reid's  Course  in  Mechanical  Drawing 8vo, 

Text-book  of  Mechanical  Drawing  and  Elementary  Machine  Design. 8vo, 

Robinson's  Principles  of  Mechanism 8vo, 

Schwamb  and  Merrill's  Elements  of  Mechanism 8vo, 

Smith's  Manual  of  Topographical  Drawing.     (McMillan.) 8vo, 

Warren's  Elements  of  Plane  and  Solid  Free-hand  Geometrical  Drawing.  i2mo, 

Drafting  Instruments  and  Operations i2mo. 

Manual  of  Elementary  Projection  Drawing i2mo, 

Manual  of  Elementary  Problems  in  the  Linear  Perspective  of  Form  and 

Shadow i2mo, 

Plane  Problems  in  Elementary  Geometry 1 2mo, 

Primary  Geometry i2mo, 

Elements  of  Descriptive  Geometry,  Shadows,  and  Perspective 8vo, 

General  Problems  of  Shades  and  Shadows 8vo, 

Elements  of  Machine  Construction  and  Drawing 8vo, 

Problems,  Theorems,  and  Examples  in  Descriptive  Geometry 8vo, 

Weisbach's  Kinematics  and  Power  of  Transmission.    (Hermann  and  Klein")8vo, 

Whelpley's  Practical  Instruction  in  the  Ait  of  Letter  Engraving i2mo, 

Wilson's  (H.  M.)  Topographic  Surveying 8vo, 

Wilson's  (V.  T.)  Free-hand  Perspective 8vo, 

Wilson's  (V.  T.)  Free-hand  Lettering 8vo, 

Woolf's  Elementary  Course  in  Descriptive  Geometry Large  8vo, 


ELECTRICITY  AND   PHYSICS. 

Anthony  and  Brackett's  Text-book  of  Physics.     (Magie.) Small  8vo, 

Anthony's  Lecture-notes  on  the  Theory  of  Electrical  Measurements.  .  .  .i2mo, 
Benjamin's  History  of  Electricity 8vo, 

Voltaic  Cell 8vo, 

Classen's  Quantitative  Chemical  Analysis  by  Electrolysis.     (Boltwood.).8vo, 

Crehore  and  Squier's  Polarizing  Photo-chronograph 8vo, 

Dawson's  "Engineering"  and  Electric  Traction  Pocket-book.  i6mo,  morocco, 
Dolezalek's    Theory    of    the    Lead    Accumulator    (Storage    Battery).      (Von 

Ende.) 12  mo, 

Duhem's  Thermodynamics  and  Chemistry.     (Burgess.) 8vo, 

Flather's  Dynamometers,  and  the  Measurement  of  Power i2mo, 

Gilbert's  De  Magnete.     (Mottelay.) 8vo, 

Hanchett's  Alternating  Currents  Explained i2tno, 

Hering's  Ready  Reference  Tables  (Conversion  Factors) i6mo,  morocco, 

Holman's  Precision  of  Measurements. 8vo, 

Telescopic    Mirror-scale  Method,  Adjustments,  and   Tests.  .  .  .Large  8vo, 

Kinzbrunner's  Testing  of  Continuous-Current  Machines 8vo, 

Landauer's  Spectrum  Analysis.     (Tingle.) 8vo, 

Le  Chatelien's  High-temperature  Measurements.  (Boudouard — Burgess.)  i2mo. 
Lob's  Electrolysis  and  Electrosynthesis  of  Organic  Compounds.  (Lorenz.)  i:nw, 

9 


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50 

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00 

3 

00 

-^Lyons's  Treatise  on  Electromagnetic  Phenomena.   Vols.  I.  and  II.  8vo,  each, 

*  Michie's  Elements  of  Wave  Motion  Relating  to  Sound  and  Light 8vo, 

Niaudet's  Elementary  Treatise  on  Electric  Batteries.     (Fishback.) i2mo, 

*  Rosenberg's  Electrical  Engineering.     (Haldane  Gee — Kinzbrunner.).  .  .8vo, 

Ryan,  Norris,  and  Hoxie's  Electrical  Machinery.     Vol.  1 8vo, 

Thurston's  Stationary  Steam-engines 8vo, 

*  Tillman's  Elementary  Lessons  in  Heat 8vo, 

Tory  and  Pitcher's  Manual  of  Laboratory  Physics Small  8vo, 

Ulke's  Modern  Electrolytic  Copper  Refining „ 8vo, 

LAW. 

*  Davis's  Elements  of  Law 8vo,  2  50 

*  Treatise  on  the  Military  Law  of  United  States 8vo,  7  00 

*  Sheep,  7  50 

Manual  for  Courts-martial i6mo,  morocco,  1  50 

Wait's  Engineering  and  Architectural  Jurisprudence 8vo,  6  00 

Sheep,  6  50 
Law  of  Operations  Preliminary  to  Construction  in  Engineering  and  Archi- 
tecture  8vo,  s  00 

Sheep,  s  50 

Law  of  Contracts 8vo,  3  00 

Winthrop's  Abridgment  of  Military  Law i2mo,  2  50 

MANUFACTURES. 

Bernadou's  Smokeless  Powder — Nitro-cellulose  and  Theory  of  the  Cellulose 

Molecule i2mo,  2  50 

Bolland's  Iron  Founder i2mo,  2  50 

"The  Iron  Founder,"  Supplement i2mo,  2  50 

Encyclopedia  of  Founding  and  Dictionary  of  Foundry  Terms  Used  in  the 

Practice  of  Moulding i2mo,  3  00 

Eissler's  Modern  High  Explosives 8vo,  4  00 

Effront's  Enzymes  and  their  Applications.     (Prescott.) 8vo,  3  00 

Fitzgerald's  Boston  Machinist i2mo,  1  00 

Ford's  Boiler  Making  for  Boiler  Makers i8mo,  1  00 

Hopkin's  Oil-chemists'  Handbook 8vo,  3  00 

Keep's  Cast  Iron 8vo,  2  50 

Leach's  The  Inspection  and  Analysis  of  Food  with  Special  Reference  to  State 

Control Large  8vo,  7  50 

Matthews's  The  Textile  Fibres 8vo,  3  50 

Metcalf's  Steel.     A  Manual  for  Steel-users nmo,  2  00 

Metcalfe's  Cost  of  Manufactures — And  the  Administration  of  Workshops. 8 vo,  5  00 

Meyer's  Modern  Locomotive  Construction 4to,  10  00 

Morse's  Calculations  used  in  Cane-sugar  Factories i6mo,  morocco,  1  50 

*  Reisig's  Guide  to  Piece-dyeing 8vo,  25  00 

Sabin's  Industrial  and  Artistic  Technology  of  Paints  and  Varnish 8vo,  3  00 

Smith's  Press-working  of  Metals 8vo,  3  00 

Spalding's  Hydraulic  Cement i2mo,  2  00 

Spencer's  Handbook  for  Chemists  of  Beet-sugar  Houses.    ...  i6mo,  morocco,  3  o<"» 

Handbook  for  Sugar  Manufacturers  and  their  Chemists.  .  1 6mo,  morocco,  -j.  oa 

Taylor  and  Thompson's  Treatise  on  Concrete,  Plain  and  Reinforced 8vo,  5  00 

Thurston's  Manual  of  Steam-boilers,  their  Designs,  Construction  and  Opera- 
tion  8vo,  5  00 

*  Walke's  Lectures  on  Explosives 8vo,  4  00 

Ware's  Manufacture  of  Sugar.     (In  press.) 

West's  American  Foundry  Practice i2mo,  2  50 

Moulder's  Text-book i2mo,  2  50 

10 


Wolff's  Windmill  ns  n  Prime  Mover Svo,     3  00 

Wood's  Rustless  Coatings:   Corrosion  and  Electrolysis  of  Iron  and  Steel.  .  8vo,    4  00 


MATHEMATICS. 

Baker's  Elliptic  Functions 8vo,  1  50 

*  Bass's  Elements  of  Differential  Calculus 1  jnw,  4  oo 

Briggs's  Elements  of  Plane  Analytic  Geometry 1  >m<>,  1  »oo 

Compton's  Manual  of  Logarithmic  Computations nmo,  1   50 

Davis's  Introduction  to  the  Logic  of  Algebra Svo,  1  50 

*  Dickson's  College  Algebra Large  nmo,  1   50 

*  Introduction  to  the  Theory  of  Algebraic  Equations.     Large  121110,  1   25 

Emch's  Introduction  to  Projective  Geometry  and  its  Applications 8vo,  2  50 

Halsted's  Elements  of  Geometry 8vo,  1    75 

Elementary  Synthetic  Geometry 8vo,  1   50 

Rational  Geometry i2mo,  1   75 

♦Johnson's  (J.  B.)  Three-place  Logarithmic  Tables:   Vest-pocket  size,  paper,  15 

100  copies  for  5  00 

*  Mounted  on  heavy  cardboard,  8  <  10  inches,  25 

10  copies  for  2  00 

Johnson's  (W.  W.)  Elementary  Treatise  on  Differential  Calculus.    Small  8vo,  n  00 

Johnson's  (W.  W.)  Elementary  Treatise  on  the  Integral  Calculus. Small  8vo,  1   50 

Johnson's  (W.  W.)  Curve  Tracing  in  Cartesian  Co-ordinates nmo,  1  00 

Johnson's  (W.  W.)  Treatise  on  Ordinary  and  Partial  Differential  Equations. 

Small  8vo,  3  50 

Johnson's  (W.  W.)  Theory  of  Errors  and  the  Method  of  Least  Squares.  nmo,  1  50 

*  Johnson's  (W.  W.)  Theoretical  Mechanics nmo,  3  00 

Laplace's  Philosophical  Essay  on  Probabilities.     (Truscott  and  Emory.),  nmo,  2  00 

*  Ludlow  and  Bass.     Elements  of  Trigonometry  and  Logarithmic  and  Other 

Tables 8vo,  3  00 

Trigonometry  and  Tables  published  separately Each,  2  00 

*  Ludlow's  Logarithmic  and  Trigonometric  Tables 8vo,  1  00 

Maurer's  Technical  Mechanics 8.    ,  4  00 

Merriman  and  Woodward's  Higher  Mathematics 8vo,  5  00 

Merriman's  Method  of  Least  Squares 8vo,  2  00 

Rice  and  Johnson's  Elementary  Treatise  on  the  Differential  Calculus. .  Sm.  8vo,  3  00 

Differential  and  Integral  Calculus.     2  vols,  in  one Small  8vo,  2  50 

Wood's  Elements  of  Co-ordinate  Geometry 8vo,  2  00 

Trigonometry:   Analytical,  Plane,  and  Spherical nmo,  1  00 


MECHANICAL   ENGINEERING. 

MATERIALS  OF  ENGINEERING,  STEAM-ENGINES  AND  BOILERS. 

Bacon's  Forge  Practice nmo,  1   50 

Baldwin's  Steam  Heating  for  Buildings nmo,  2  50 

Barr's  Kinematics  of  Machinery 8vo,  2  50 

*  Bartlett's  Mechanical  Drawing 8vo,  3  00 

*  "  "  "        Abridged  Ed 8vo,     1  50 

Benjamin's  Wrinkles  and  Recipes nmo,     2  00 

Carpenter's  Experimental  Engineering 8vo,    6  00 

Heating  and  Ventilating  Buildings 8vo,    4  00 

Cary's  Smoke  Suppression  in  Plants  using  Bituminous  Coal.     (In  Prepara- 
tion.) 

Clerk's  Gas  and  Oil  Engine Small  8vo,    4  00 

Coolidge's  Manual  of  Drawing 8vo,  paper,     1  00 

Coolidge  and  Freeman's  Elements  of  General  Drafting  for  Mechanical  En- 
gineers  Oblong  4to,     2  50 

11 


Cromwell's  Treatise  on  Toothed  Gearing i2mo,  i  50 

Treatise  on  Belts  and  Pulleys i2mo,  1  50 

Durley's  Kinematics  of  Machines 8vo,  4  00 

Flather's  Dynamometers  and  the  Measurement  of  Power i2mo,  3  00 

""  Rope  Driving i2mo,  2  00 

Gill's  Gas  and  Fuel  Analysis  for  Engineers i2mo,  1  25 

Hall's  Car  Lubrication i2mo,  1  00 

Hering's  Ready  Reference  Tables  (Conversion  Factors) i6mo,  morocco,  2  50 

Hutton's  The  Gas  Engine 8vo,  5  00 

Jamison's  Mechanical  Drawing 8vo,  2  50 

Jones's  Machine  Design : 

Part  I.     Kinematics  of  Machinery 8vo,  1  50 

Part  II.     Form,  Strength,  and  Proportions  of  Parts. .  „ 8vo,  3  00 

Kent's  Mechanical  Engineers'  Pocket-book i6mo,  morocco,  5  00 

Kerr's  Power  and  Power  Transmission 8vo,  2  00 

Leonard's  Machine  Shop,  Tools,  and  Methods.     (In  press.) 

Lorenz's  Modern  Refrigerating  Machinery.     (Pope,  Haven,  and  Dean.)     (In  press.) 

MacCord's  Kinematics;   or,  Practical  Mechanism 8vo,  5  00 

Mechanical  Drawing 4to,  4  00 

Velocity  Diagrams 8vo,  1  50 

Mahan's  Industrial  Drawing.     (Thompson.) 8vo,  3  50 

Poole's  Calorific  Power  of  Fuels 8vo,  3  00 

Reid's  Course  in  Mechanical  Drawing 8vo,  2  00 

Text-book  of  Mechanical  Drawing  and  Elementary  Machine  Design. 8vo,  3  00 

Richard's  Compressed  Air i2mo,  1  50 

Robinson's  Principles  of  Mechanism 8vo,  3  00 

Schwamb  and  Merrill's  Elements  of  Mechanism 8vo,  3  00 

Smith's  Press-working  of  Metals 8vo,  3  00 

Thurston's   Treatise    on   Friction  and   Lost   Work   in   Machinery   and    Mill 

Work 8vo,  3  00 

Animal  as  a  Machine  and  Prime  Motor,  and  the  Laws  of  Energetics .  1 2mo,  1  00 

Warren's  Elements  of  Machine  Construction  and  Drawing .8vo,  7  50 

Weisbach's    Kinematics    and    the    Power    of    Transmission.     (Herrmann — 

Klein.) 8vo,  5  00 

Machinery  of  Transmission  and  Governors.     (Herrmann — Klein.).  .8vo,  5  00 

Wolff's  Windmill  as  a  Prime  Mover 8vo,  3  00 

Wood's  Turbines 8vo,  2  50 


MATERIALS   OF   ENGINEERING. 

Bovey's  Strength  of  Materials  and  Theory  of  Structures 8vo,  7  50 

Burr's  Elasticity  and  Resistance  of  the  Materials  of  Engineering.    6th  Edition. 

Reset 8vo,  7  50 

Church's  Mechanics  of  Engineering , 8vo,  6  00 

Johnson's  Materials  of  Construction 8vo,  6  00 

Keep's  Cast  Iron 8vo,  2  50 

Lanza's  Applied  Mechanics 8vo,  7  50 

Martens 's  Handbook  on  Testing  Materials.     (Henning.) 8vo,  7  50 

Merriman's  Text-book  on  the  Mechanics  of  Materials 8vo,  4  00 

Strength  of  Materials i2mo,  1  00 

Metcalf 's  Steel.     A  manual  for  Steel-users i2mo.  2  00 

Sabin's  Industrial  and  Artistic  Technology  of  Paints  and  Varnish 8vo,  3  00 

Smith's  Materials  of  Machines i2mo,  1  00 

Thurston's  Materials  of  Engineering 3  vols.,  8vo,  8  00 

Part  II.     Iron  and  Steel 8vo,  3  50 

Part  HI.     A  Treatise  on  Brasses,  Bronzes,  and  Other  Alloys  and  their 

Constituents 8vo,  2  50 

Text-book  of  the  Materials  of  Construction 8vo,  5  <>• 

12 


Wood's  (De  V.i  Treatise  on  the  Resistance  of  Materials  and  tin  Appendix  on 
the  Presei"vation  of  Timber 8vo, 

Wood's  (De  V.)  Elements  of  Analytical  Mechanics. 8vo, 

food's  (M.  P.)  Rustless  Coatings:  Corrosion  and  Electrolysis  of  Iron  and 
SteeL 8vo, 


STEAM-ENGINES  AND  BOILERS. 


Berry's  Temperature-entropy  Diagram 1 21110 

Carnot's  Reflections  on  the  Motive  Power  of  Heat     (Thurston.) nmo 

Dawson's  "Engineering"  and  Electric  Traction  Pocket-book. ..  .i6mo,  mor. 

Ford's  Boiler  Making  for  Boiler  Makers i8mo 

Goss's  Locomotive  Sparks 8vo 

Hemenway's  Indicator  Practice  and  Steam-engine  Economy i2mo 

Hutton's  Mechanical  Engineering  of  Power  Plants 8vo 

Heat  and  Heat-engines 8vo 

Kent's  Steam  boiler  Economy 8vo 

Kneass's  Practice  and  Theory  of  the  Injector 8vo 

MacCord's  Slide-valves 8vo 

Meyer's  Modern  Locomotive  Construction 4to 

Peabody's  Manual  of  the  Steam-engine  Indicator i2mo 

Tables  of  the  Properties  of  Saturated  Steam  and  Other  Vapors 8vo 

Thermodynamics  of  the  Steam-engine  and  Other  Heat-engines 8vo 

Valve-gears  for  Steam-engines 8vo 

Peabody  and  Miller's  Steam-boilers 8vo 

Pray's  Twenty  Years  with  the  Indicator Large  8vo 

Pupin's  Thermodynamics  of  Reversible  Cycles  in  Gases  and  Saturated  Vapors 

(Osterberg. ) i2mo 

Reagan's  Locomotives:   Simple   Compound,  and  Electric i2mo 

Rontgen's  Principles  of  Thermodynamics.     (Du  Bois.) 8vo 

Sinclair's  Locomotive  Engine  Running  and  Management i2mo 

Smart's  Handbook  of  Engineering  Laboratory  Practice i2mo 

%iow's  Steam-boiler  Practice 8vo 

Spangler's  Valve-gears 8vo 

Notes  on  Thermodynamics i2mo 

Spangler,  Greene,  and  Marshall's  Elements  of  Steam-engineering 8vo 

Thurston's  Handy  Tables 8vo 

Manual  of  the  Steam-engine 2  vols.,  8vo 

Part  I.     History,  Structure,  and  Theory 8vo 

Part  H.     Design,  Construction,  and  Operation 8vo 

Handbook  of  Engine  and  Boiler  Trials,  and  the  Use  of  the  Indicator  and 

the  Prony  Brake 8vo 

Stationary  Steam-engines 8vo 

Steam-boiler  Explosions  in  Theory  and  in  Practice i2mo 

Manual  of  Steam-boilers,  their  Designs,  Construction,  and  Operation 8vo 

Weisbach's  Heat.  Steam,  and  Steam-engines.     (Du  Bois.) 8vo 

Whitham's  Steam-engine  Design 8vo 

Wilson's  Treatise  on  Steam-boilers.     (Elather.) i6mo 

Wood's  Thermodynamics,  Heat  Motors,  and  Refrigerating  Machines ...  8vo 


MECHANICS  AND  MACHINERY. 


Barr's  Kinematics  of  Machinery 8vo, 

Bovey's  Strength  of  Materials  and  Theory  of  Structures 8vo, 

Chase's  The  Art  of  Pattern-making i2mo, 

Church's  Mechanics  of  Engineering . .  .8vo, 

13 


2  50 
7  50 
2  50 

6  00 


Church's  Notes  and  Examples  in  Mechanics 8vo,  2  00 

Compton's  First  Lessons  in  Metal-working ._ i2mo,  1  50 

Compton  and  De  Groodt's  The  Speed  Lathe nmo,  1  50 

Cromwell's  Treatise  on  Toothed  Gearing nmo,  1  50 

Treatise  on  Belts  and  Pulleys i2mo,  1  50 

Dana's  Text-book  of  Elementary  Mechanics  for  Colleges  and  Schools.  .i2mo,  1  50 

Dingey's  Machinery  Pattern  Making nmo,  2  00 

Dredge's  Record  of  the  Transportation  Exhibits  Building  of  the  World's 

Columbian  Exposition  of  1893 4to  half  morocco,  5  00 

Du  Bois's  Elementary  Principles  of  Mechanics: 

Vol.      I.     Kinematics , . , 8vo,  3  50 

Vol.    II.     Statics 8vo,  400 

VoL  in.     Kinetics . 8vo,  3  50 

Mechanics  of  Engineering.     Vol.    I Small  4to,  7  so 

VoL  II Small  410,  10  00 

Durley's  Kinematics  of  Machines 8vo,  4  00 

Fitzgerald's  Boston  Machinist i6mo,  1  00 

Flather's  Dynamometers,  and  the  Measurement  of  Power i2mo,  3  00 

Rope  Driving nmo,  2  00 

Goss's  Locomotive  Sparks 8vo,  2  00 

Hall's  Car  Lubrication nmo,  1  00 

Holly's  Art  of  Saw  Filing i8mo,  75 

James's  Kinematics  of  a  Point  and  the  Rational  Mechanics  of  a  Particle.  Sm.8vo,2  00 

*  Johnson's  (W.  W.)  Theoretical  Mechanics nmo,  3  00 

Johnson's  (L.  J.)  Statics  by  Graphic  and  Algebraic  Methods 8vo,  2  00 

Jones's  Machine  Design: 

Part    I.     Kinematics  of  Machinery 8vo,  1  50 

Part  n.     Form,  Strength,  and  Proportions  of  Parts 8vo,  3  00 

Kerr's  Power  and  Power  Transmission 8vo,  2  00 

Lanza's  Applied  Mechanics 8vo,  7  50 

Leonard's  Machine  Shop,  Tools, -and  Methods.     (In  press.) 

Lorenz's  Modern  Refrigerating  Machinery.      (Pope,  Haven,  and  Dean.)      (In  press.) 

MacCord's  Kinematics;  or,  Practical  Mechanism 8vo,  5  00 

Velocity  Diagrams 8vo,  1  50 

Maurer's  Technical  Mechanics 8vo,  4  00 

Merriman's  Text-book  on  the  Mechanics  of  Materials 8vo,  4  00 

*  Elements  of  Mechanics nmo,  1  00 

*  Michie's  Elements  of  Analytical  Mechanics 8vo,  4  00 

Heagan's  Locomotives:   Simple,  Compound,  and  Electric nmo,  2  50 

Reid's  Course  in  Mechanical  Drawing 8vo,  2  00 

Text-book  of  Mechanical  Drawing  and  Elementary  Machine  Design. 8vo,  3  00 

Richards's  Compressed  Air nmo,  1  50 

Robinson's  Principles  of  Mechanism 8vo,  3  00 

Ryan,  Norris,  and  Hoxie's  Electrical  Machinery.     Vol.  1 8vo,  2  50 

Schwamb  and  Merrill's  Elements  of  Mechanism 8vo,  3  00 

Sinclair's  Locomotive-engine  Running  and  Management nmo,  2  00 

Smith's  (0.)  Press-working  of  Metals- 8vo,  3  00 

Smith's  (A.  W.)  Materials  of  Machines nmo,  1  00 

Spangler,  Greene,  and  Marshall's  Elements  of  Steam-engineering 8vo,  3  00 

Thurston's  Treatise  on  Friction  and  Lost  Work  in    Machinery  and    Mill 

Work 8vo,  3  00 

Animal  as  a  Machine  and  Prime  Motor,  and  the  Laws  of  Energetics. 

nmo,  1  00 

Warren's  Elements  of  Machine  Construction  and  Drawing 8vo,  7  50 

Weisbach's  Kinematics  and  Power  of  Transmission.    (Herrmann — Klein.  ).8vo,  5  00 

Machinery  of  Transmission  and  Governors.      (Herrmann — Klein. ).8vo,  5  00 

Wood's  Elements  of  Analytical  Mechanics 8vo,  3  00 

Principles  of  Elementary  Mechanics nmo,  1  25 

Turbines 8vo.  2  50 

The  World's  Columbian  Exposition  of  1893 4to>  *  0O 

14 


3   50 


METALLURGY. 

Fgleston's  Metallurgy  of  Silver,  Gold,  and  Mercury: 

Vol.    I.     Silver 8v.. 

Vol.  II.     Gold  and  Mercury Sv„  _   C.(J 

**  Iles's  Lead-smelting.     (Postage  o  cents  additional.) i2mo!  2  50 

Keep's  Cast  Iron gvo>  ,   go 

Kunhardt's  Practice  of  Ore  Dressing  in  Europe 8vo,  1  *o 

Lc  Chatelier's  High-temperature  Measuremepts.  (  Boudouard— Burgess,  inmo,  3  00 

Metcalf's  Steel.     A  Manual  for  Steel-users     I2mo'  2  0<> 

Smith's  Materials  of  Machines i2mo  1  00 

Thurston's  Materials  of  Engineering.     In  Three  Parts 8vo!  8  00 

Part    II.     Iron  and  Steel 8vo 

Part  III.     A  Treatise  on  Brasses,  Bronzes,  and  Other  Alloys  and  their 

Constituents gvo.  2  50 

Ulke's  Modern  Electrolytic  Copper  Refining gVOi  3  0O 

MINERALOGY. 

Barringer's  Description  of  Minerals  of  Commercial  Value.    Oblong,  morocco,  2  50 

Boyd's  Resources  of  Southwest  Virginia gvo'  ,  0O 

Map  of  Southwest  Virignia Pocket-book  fora.  2  00 

Brush's  Manual  of  Determinative  Mineralogy.     (Penfield.) 8vo  4  o» 

Chester's  Catalogue  of  Minerals .'  .8vo.  paper,  1  oc 

Cloth,  1   25 

Dictionary  of  the  Names  of  Minerals 8vo,  3  „ 

Dana's  System  of  Mineralogy Large  8vo,  half  leather!  12  50 

First  Appendix  to  Dana's  New  "  System  of  Mineralogy." Large  8vo,  1  00 

Text-book  of  Mineralogy gv0('  OQ 

Minerals  and  How  to  Study  Them i2mo!  1  50 

Catalogue  of  American  Localities  of  Minerals Large  8vo|  1  00 

Manual  of  Mineralogy  and  Petrography i2mo'.  2  00 

Douglas's  Untechnical  Addresses  on  Technical  Subjects i2mo,  1  00 

Eakle's  Mineral  Tables a     ' 

_,                                                                                     oVO,  I     2  c 

Egleston  s  Catalogue  of  Minerals  and  Synonyms 8vo  2  so 

Hussak's  The  Determination  of  Rock-forming  Minerals.    (Smith. ). Small  8vo.'  2  00 

Merrill's  Non-metallic  Minerals:   Their  Occurrence  and  Uses 8vo  4  00 

*  Ponfield's  Notes  on  Determinative  Mineralogy  and  Record  of  Mineral  Tests' 


8vo   paper,    o  50 
Roscabusch's    Microscopical   Physiography   or   the    Rock-making  Minerals 
(Iddings.  1 g 

*  Tillman's  Text-book  of  Important  Minerals  and  Rocks 8vo      2  00 

Williams's  Manual  of  Lithology.  .  "  o_  ' 

6J ovo,    3  00 

MINING. 

ieard's  Ventilation  of  Mines. 

b  _  • i2mo     2  so 

Boyd  s  Resources  of  Southwest  Virginia  g 

M6p  of  Southwest  Virginia V/.V.V/.'.'.V.'.'.PockeY  bookform.'    I  00 

Douglao  s  Untechnical  Addresses  on  Technical  Subjects I2mo      1  00 

♦Drinker's  Tunneling,  Explosive  Compounds,  and  Rock  Drills   .410  hf  mor  '  2s  00 

Eissler's  Modern  High  Explosives 8vo' 

Fowler's  Sewage  Works  Analyses 

Goodyear's  Coal-mines  of  the  Western  Coast  of  the  United  States 
Ihlseng's  Manual  of  Mining  „ 

*»  T,    ,    -       ,  ,  .  & ovo.     5  00 

**  lies  s  Lead-smelting.     (Postage  9c  additionaL).  ..    .  I2mo      2   «-„ 

Kunhardt's  Practice  of  Ore  Dressing  in  Europe 8vo'     iso 

O'Driscoll's  Notes  on  the  Treatment  of  Gold  Ores 8vo      2  00 

*  Walke's  Lectures  on  Explosives.  a,    ' 

Wilson's  Cyanide  Processes .'..".".'. ".".".". '. '. '. '. '. '. '. .'.'.'.. i ,^'     ,   °° 

ChicBlnation  Process. . . 

iamo,    1  50 

15 


00 

1 2  mo      2  00 


Wilson's  HydrauL^,  and  Placer  Mining i2mo,  2  00 

Treatise  on  Practical  and  Theoretical  Mine  Ventilation T2mo,  1  25 

SANITARY  SCIENCE. 

Folwell's  Sewerage.     (Designing,  Construction,  and  Maintenance.) 8vo,  3  oe 


4 


3 


Water-supply  Engineering 8vo, 

Fuertes's  Water  and  Public  Health i2mo,  1  50 

Water-filtration  Works i2mo,  2  50 

Gerhard's  Guide  to  Sanitary  House-inspection i6mo,  1  00 

Goodrich's  Economic  Disposal  of  Town's  Refuse Demy  8vo,  3  50 

Hazen's  Filtration  of  Public  Water-supplies 8vo, 

Leach's  The  Inspection  and  Analysis  of  Food  with  Special  Reference  to  State 

Control 8vo,  7  50 

Mason's  Water-supply.  (Considered  principally  from  a  Sanitary  Standpoint)  8vo,  4  00 

Examination  of  Water.     (Chemical  and  Bacteriological.) i2mo,  1  25 

Merriman's  Elements  of  Sanitary  Engineering 8vo,  2  00 

Ogden's  Sewer  Design i2mo,  2  00 

Prescott  and  Winslow's  Elements  of  Water  Bacteriology,  with  Special  Refer- 
ence to  Sanitary  Water  Analysis i2mo,  1  25 

*  Price's  Handbook  on  Sanitation i2mo,  1  50 

Richards's  Cost  of  Food.     A  Study  in  Dietaries i2mo,  1  00 

Cost  of  Living  as  Modified  by  Sanitaiy  Science i2mo,  1  00 

Richards  and  Woodman's  Air,  Water,  and  Food  from  a  Sanitary  Stand- 
point  8vo,  2  00 

*  Richards  and  Williams's  The  Dietary  Computer 8vo,  1  50 

Rideal's  Sewage  and  Bacterial  Purification  of  Sewage 8vo,  3  50 

Turneaure  and  Russell's  Public  Water-supplies 8vo,  5  00 

Von  Behring's  Suppression  of  Tuberculosis.     (Bolduan.) i2mo,  1  00 

Whipple's  Microscopy  of  Drinking-water 8vo,  3  50 

Woodhull's  Notes  on  Military  Hygiene i6mo,  1  50 

MISCELLANEOUS. 

De  Fursac's  Manual  of  Psychiatry.     (Rosanoff  and  Collins.).  .  .  .Large  i2mo,    2  50 
Emmons's  Geological  Guide-book  of  the  Rocky  Mountain  Excursion  of  the 

International  Congress  of  Geologists Large  8vo,     1  50 

Ferrel's  Popular  Treatise  on  the  Winds 8vo.    4  00 

Haines's  American  Railway  Management i2mo, 

Mott's  Composition,  Digestibility,  and  Nutritive  Value  of  Food.  Mounted  chart, 

Fallacy  of  the  Present  Theory  of  Sound i6mo, 

Ricketts's  History  of  Rensselaer  Polytechnic  Institute,  1824-1894.  .Small  8vo, 

Rostoski's  Serum  Diagnosis.     (Bolduan.) i2mo, 

Rotherham's  Emphasized  New  Testament Large  8vo, 

Steel's  Treatise  on  the  Diseases  of  the  Dog 8vo, 

Totten's  Important  Question  in  Metrology 8vo, 

The  World's  Columbian  Exposition  of  1893 4to, 

Von  Behring's  Suppression  of  Tuberculosis.     (Bolduan.) i2mo, 

Winslow's  Elements  of  Applied  Microscopy i2mo, 

Worcester  and  Atkinson.      Small  Hospitals,  Establishment  and  Maintenance; 

Suggestions  for  Hospital  Architecture :  Plans  for  Small  Hospital .  1 2mo ,    125 

HEBREW  AND   CHALDEE  TEXT-BOOKS. 

Green's  Elementary  Hebrew  Grammar i2mo,  I  25 

Hebrew  Chrestomathy 8vo,  2  00 

Gesenius's  Hebrew  and  Chaldee  Lexicon  to,  the  Old  Testament  Scriptures. 

(Tregelles.) Small  4to,  half  morocco,  5  00 

Letteris's  Hebrew  Bible 8vo»  2  25 


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